Clinical trial NCT03325439
Conditions: Electroencephalographic Neonatal Seizures
Keywords: Electroencephalographic neonatal seizures Brivaracetam Epilepsy ENS Newborns Pharmacokinetic
Sponsor: UCB Biopharma SRL
Start date: 2019-05-07; Completion date: 2021-05-29
Enrollment: 9 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The purpose of the study is to evaluate the pharmacokinetics (PK) of brivaracetam (BRV) in neonates who have seizures that are not adequately controlled with previous antiepileptic drug (AED) treatment, and to identify the optimal BRV dose (Exploratory Cohort) for the treatment of subjects enrolled into the Confirmatory Cohorts of this study.

Detailed description:

Arms: arm 1: Exploratory Cohort and Confirmatory Cohorts
Interventions: intervention 1: Brivaracetam (BRV) intravenous (iv) intervention 2: Brivaracetam (BRV) oral
Intervention descriptions: intervention 1: Exploratory Cohort:

Subjects will be dosed with BRV (0.5 mg/kg twice daily (bid)) according to the sites standard procedures. Treatment with 1 or more of the following antiepileptic drugs (AEDs): phenobarbital (PB), midazolam (MDZ), phenytoin (PHT), levetiracetam (LEV), or lidocaine (LDC) (first-line, second-line, or subsequent treatment) will continue in parallel with BRV treatment.

Confirmatory Cohort:

For subjects who enter the Confirmatory Cohorts, for the strength of BRV 1 mg/kg bid (2 mg/kg/day) has been determined based on the Pharmacokinetic (PK) findings of the Exploratory Cohort. Based on further monitoring of PK and safety findings dosing may be adjusted as new data are available. Administration of BRV is proposed as approximately 15-minute intravenous (iv) infusions. Treatment with previous antiepileptic drugs is permitted to continue if the subject is on a stable dose from 1 hour prior to initiation of the BRV treatment. intervention 2: Subjects can switch from intravenous (iv) to oral brivaracetam (BRV) at any time during the BRV Extension Period

Protocol documents:
Prot_000.pdf: 
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PROTOCOL N01349 AMENDMENT 7 
A MULTICENTER, OPEN-LABEL, SINGLE-ARM STUDY TO 
EVALUATE THE PHARMACOKINETICS, EFFICACY, AND 
SAFETY OF BRIVARACETAM IN NEONATES WITH 
REPEATED ELECTROENCEPHALOGRAPHIC SEIZURES 
PHASE 2/3 
EudraCT Number: 2015-002756-27 
Sponsor: 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Protocol/Amendment number 
Date 
Type of amendment 
Final Protocol 
14 Oct 2016 
Not applicable 
Protocol Amendment (1.0) 
14 Dec 2016 
Non-Substantial 
Protocol Amendment (2.0) 
28 Feb 2017 
Non-Substantial 
Protocol Amendment (2.1, Germany) 
19 Jul 2017 
Non-Substantial 
Protocol Amendment (2.2, Czech Republic) 
19 Jul 2017 
Non-Substantial 
Protocol Amendment (3.0) 
23 Oct 2017 
Non-Substantial 
Protocol Amendment (4.0) 
22 Jan 2018 
Non-Substantial 
Protocol Amendment (5.0) 
10 Oct 2019 
Substantial 
Protocol Amendment (6.0) 
28 Oct 2019 
Non-Substantial 
Protocol Amendment (6.1, Germany) 
08 Nov 2019 
Non-Substantial 
Protocol Amendment (6.2, Czech Republic) 
08 Nov 2019 
Non-Substantial 
Protocol Amendment (6.3, France) 
07 Oct 2020 
Substantial 
Protocol Amendment (6.4, Czech Republic) 
10 Nov 2020 
Substantial 
Protocol Amendment (6.5, Germany) 
02 Dec 2020 
Substantial 
Protocol Amendment (7.0) 
24 May 2021 
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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STUDY CONTACT INFORMATION 
Sponsor 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
 
Principal/Coordinating Investigator 
Name: 
Ronit Pressler, 
 
Affiliation: 
University College London 
Address: 
Gower Street 1  
London, WC1E 6BT 
United Kingdom 
Phone: 
 
Fax: 
 
Sponsor Study Physician 
Name: 
, 
  
Address: 
UCB BioSciences, Inc. 
8010 Arco Corporate Drive 
 
Raleigh, NC 27617 
USA 
Phone: 
 
Fax: 
  
Clinical Project Manager 
Name: 
, 
 
Address: 
Alfred-Nobel-Strasse 10 
40789 Monheim 
GERMANY 
Phone: 
 
Fax: 
 
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Clinical Trial Biostatistician 
Name: 
, 
  
Address: 
UCB BioSciences, Inc.  
8010 Arco Corporate Drive, 
 
Raleigh, NC 27617 
USA 
Phone: 
 
Fax: 
 
Clinical Monitoring Contract Research Organization 
Name: 
PRA Health Sciences 
Address: 
Green Park 
500 South Oak Way 
Reading, RG2 6AD 
United Kingdom 
Phone: 
+44 118 918 1000 
Fax: 
+44 118 918 1001 
Data Monitoring Committee 
Name: 
Affiliation/Job title: 
 
 
Pediatric Clinical Pharmacologist 
 
Pediatric Neonatologist 
 
Pediatric Neonatologist 
 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
Europe: +32 238 66561  
Email 
PSRapidalert@ucb.com 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................. 10 
1 
SUMMARY ..................................................................................................................... 12 
2 
INTRODUCTION ........................................................................................................... 15 
2.1 
Epidemiology and treatment of targeted disease ......................................................... 15 
2.2 
Background information regarding product................................................................. 15 
2.3 
Rationale for the study ................................................................................................. 17 
3 
STUDY OBJECTIVES .................................................................................................... 18 
3.1 
Primary objective ......................................................................................................... 18 
3.2 
Secondary objectives ................................................................................................... 18 
4 
STUDY VARIABLES ..................................................................................................... 18 
4.1 
PK variables (Exploratory and Confirmatory Cohorts) ............................................... 18 
4.1.1 
Primary PK variable ............................................................................................ 18 
4.1.2 
Other PK variables ............................................................................................... 18 
4.2 
Efficacy variables (Confirmatory Cohorts only) ......................................................... 19 
4.2.1 
Secondary efficacy variables ............................................................................... 19 
4.2.2 
Other efficacy variables ....................................................................................... 20 
4.3 
Safety variables (Exploratory and Confirmatory Cohorts) .......................................... 21 
4.3.1 
Secondary safety variable .................................................................................... 21 
4.3.2 
Other safety variables .......................................................................................... 21 
5 
STUDY DESIGN ............................................................................................................. 22 
5.1 
Study description ......................................................................................................... 22 
5.1.1 
Exploratory Cohort .............................................................................................. 24 
5.1.2 
Confirmatory Cohorts .......................................................................................... 25 
5.1.3 
Study duration per subject ................................................................................... 28 
5.1.4 
Planned number of subjects and sites .................................................................. 28 
5.1.5 
Anticipated regions and countries ....................................................................... 29 
5.2 
Schedule of study assessments..................................................................................... 29 
5.3 
Schematic diagrams ..................................................................................................... 40 
5.4 
Rationale for study design and selection of dose ......................................................... 45 
5.4.1 
Rationale for study design ................................................................................... 45 
5.4.2 
Rationale for dose selection ................................................................................. 45 
6 
SELECTION AND WITHDRAWAL OF SUBJECTS ................................................... 47 
6.1 
Inclusion criteria .......................................................................................................... 47 
6.2 
Exclusion criteria ......................................................................................................... 47 
6.3 
Withdrawal criteria ...................................................................................................... 48 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria ........................ 49 
7 
STUDY TREATMENTS ................................................................................................. 50 
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7.1 
Description of investigational medicinal products ...................................................... 50 
7.2 
Treatments to be administered ..................................................................................... 50 
7.3 
Packaging ..................................................................................................................... 51 
7.4 
Labeling ....................................................................................................................... 51 
7.5 
Handling and storage requirements ............................................................................. 51 
7.6 
Drug accountability ...................................................................................................... 51 
7.7 
Procedures for monitoring subject compliance ............................................................ 52 
7.8 
Concomitant treatments and medications .................................................................... 52 
7.8.1 
Permitted concomitant treatments (medications and therapies) .......................... 52 
7.8.2 
Prohibited concomitant treatments (medications and therapies) ......................... 53 
7.8.3 
Rescue medication ............................................................................................... 53 
7.9 
Blinding........................................................................................................................ 53 
7.10 
Randomization and numbering of subjects .................................................................. 53 
8 
STUDY PROCEDURES BY VISIT ............................................................................... 53 
8.1 
Exploratory Cohort ...................................................................................................... 54 
8.1.1 
Screening Period .................................................................................................. 54 
8.1.2 
Evaluation Period ................................................................................................. 55 
8.1.3 
BRV Extension Period ......................................................................................... 56 
8.1.3.1 
Extension Period Visit 1 ............................................................................ 57 
8.1.3.2 
Extension Period Visit 2 ............................................................................ 57 
8.1.3.3 
Unscheduled Visit ..................................................................................... 58 
8.1.3.4 
Telephone Contact ..................................................................................... 58 
8.1.4 
Safety Follow-Up Period ..................................................................................... 58 
8.2 
Confirmatory Cohorts .................................................................................................. 59 
8.2.1 
Screening Period .................................................................................................. 59 
8.2.1.1 
Baseline Period .......................................................................................... 59 
8.2.2 
Evaluation Period ................................................................................................. 60 
8.2.3 
BRV Extension Period ......................................................................................... 62 
8.2.3.1 
Extension Period Visit 1 ............................................................................ 63 
8.2.3.2 
Extension Period Visit 2 ............................................................................ 63 
8.2.3.3 
Unscheduled Visit ..................................................................................... 64 
8.2.3.4 
Telephone Contact ..................................................................................... 64 
8.2.4 
Down-Titration Period ......................................................................................... 64 
8.2.5 
Safety Follow-Up Period ..................................................................................... 65 
9 
ASSESSMENT OF PHARMACOKINETIC VARIABLES ........................................... 65 
9.1 
Pharmacokinetic sampling and handling ..................................................................... 65 
9.2 
Pharmacokinetic sample shipment ............................................................................... 67 
10 ASSESSMENT OF EFFICACY ...................................................................................... 67 
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10.1 
Assessment of the secondary efficacy variables (Confirmatory Cohort[s] only) ........ 67 
10.2 
Assessment of other efficacy variables ........................................................................ 68 
10.3 
Seizure burden ............................................................................................................. 69 
11 ASSESSMENT OF SAFETY .......................................................................................... 69 
11.1 
Adverse events ............................................................................................................. 69 
11.1.1 
Definitions ........................................................................................................... 69 
11.1.1.1 
Adverse event ............................................................................................ 69 
11.1.1.2 
Serious adverse event ................................................................................ 70 
11.1.1.3 
Adverse events of special interest ............................................................. 72 
11.1.2 
Procedures for reporting and recording adverse events ....................................... 72 
11.1.2.1 
Description of adverse events .................................................................... 75 
11.1.2.2 
Rule of repetition of an adverse event ....................................................... 75 
11.1.2.3 
Additional procedures for reporting serious adverse events ..................... 75 
11.1.2.4 
Immediate reporting of adverse events...................................................... 76 
11.1.3 
Follow-up of adverse events ................................................................................ 76 
11.1.4 
Suspected transmission of an infectious agent .................................................... 76 
11.1.5 
Overdose of investigational medicinal product ................................................... 76 
11.1.6 
Safety signal detection ......................................................................................... 77 
11.2 
Laboratory measurements ............................................................................................ 77 
11.2.1 
Evaluation of PDILI ............................................................................................ 79 
11.2.1.1 
Consultation with Medical Monitor and local hepatologist ...................... 81 
11.2.1.2 
Immediate action: determination of IMP discontinuation ......................... 81 
11.2.1.3 
Testing: identification/exclusion of alternative etiology ........................... 81 
11.2.1.4 
Follow-up evaluation ................................................................................. 83 
11.3 
Other safety measurements .......................................................................................... 83 
11.3.1 
Physical and neurological examinations .............................................................. 83 
11.3.2 
Medical history including Apgar score ................................................................ 84 
11.3.3 
Vital signs ............................................................................................................ 84 
11.3.4 
Biometric parameters ........................................................................................... 84 
11.3.5 
N-PASS ................................................................................................................ 84 
11.3.6 
Video-EEG Parameters ........................................................................................ 84 
11.3.7 
HIE (Thompson score) ........................................................................................ 85 
11.3.8 
Withdrawal and rebound phenomena .................................................................. 85 
11.3.9 
Mechanical ventilation ......................................................................................... 85 
11.3.10 
Bayley Scales of Infant and Toddler Development, Third Edition ..................... 85 
12 STUDY MANAGEMENT AND ADMINISTRATION ................................................. 86 
12.1 
Adherence to protocol .................................................................................................. 86 
12.2 
Monitoring ................................................................................................................... 86 
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12.2.1 
Definition of source data ..................................................................................... 86 
12.2.2 
Source data verification ....................................................................................... 87 
12.3 
Data handling ............................................................................................................... 87 
12.3.1 
Case Report form completion .............................................................................. 87 
12.3.2 
Database entry and reconciliation ........................................................................ 87 
12.3.3 
Subject Screening and Enrollment log/Subject Identification Code list.............. 87 
12.4 
Termination of the study .............................................................................................. 88 
12.5 
Archiving and data retention ........................................................................................ 88 
12.6 
Audit and inspection .................................................................................................... 88 
12.7 
Good Clinical Practice ................................................................................................. 88 
13 STATISTICS ................................................................................................................... 89 
13.1 
Definition of analysis sets ............................................................................................ 89 
13.2 
General statistical considerations ................................................................................. 89 
13.3 
Pharmacokinetic variable analysis ............................................................................... 89 
13.3.1 
Exploratory Cohort .............................................................................................. 89 
13.3.2 
Confirmatory Cohorts .......................................................................................... 90 
13.4 
Safety analyses ............................................................................................................. 90 
13.5 
Planned efficacy analyses ............................................................................................ 90 
13.5.1 
Analysis of the secondary efficacy variables ....................................................... 90 
13.5.2 
Analysis of the other efficacy variables ............................................................... 92 
13.6 
Handling of protocol deviations................................................................................... 93 
13.7 
Handling of dropouts or missing data .......................................................................... 93 
13.8 
Planned PK data review and safety data monitoring ................................................... 93 
13.8.1 
Exploratory Cohort .............................................................................................. 93 
13.8.2 
Confirmatory Cohorts .......................................................................................... 93 
13.8.3 
DMC and stopping rules ...................................................................................... 94 
13.9 
Determination of sample size ....................................................................................... 94 
14 ETHICS AND REGULATORY REQUIREMENTS ...................................................... 94 
14.1 
Informed consent ......................................................................................................... 94 
14.2 
Subject identification cards .......................................................................................... 95 
14.3 
Independent Ethics Committees .................................................................................. 95 
14.4 
Subject privacy............................................................................................................. 96 
14.5 
Protocol amendments ................................................................................................... 96 
15 FINANCE, INSURANCE, AND PUBLICATION ......................................................... 96 
16 REFERENCES ................................................................................................................ 97 
17 APPENDICES ............................................................................................................... 100 
17.1 
Protocol Amendment 1 .............................................................................................. 100 
17.2 
Protocol Amendment 2 .............................................................................................. 122 
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17.3 
Protocol Amendment 3 .............................................................................................. 135 
17.4 
Protocol Amendment 4 .............................................................................................. 173 
17.5 
Protocol Amendment 5 .............................................................................................. 174 
17.6 
Protocol Amendment 6 .............................................................................................. 239 
17.7 
Protocol Amendment 7 .............................................................................................. 241 
18 DECLARATION AND SIGNATURE OF INVESTIGATOR ..................................... 253 
19 SPONSOR DECLARATION ........................................................................................ 254 
 
LIST OF TABLES 
Table 5‒1: 
Schedule of study assessments – Screening and Evaluation Periods 
(Exploratory Cohort) ........................................................................................ 30 
Table 5‒2: 
Schedule of study assessments – Screening and Evaluation Periods 
(Confirmatory Cohorts) ................................................................................... 32 
Table 5-3: 
Schedule of study assessments - BRV Extension Period and Safety 
Follow-Up Period (Exploratory and Confirmatory Cohorts)........................... 37 
Table 5‒4: 
Schedule for PK Sampling (Exploratory Cohort) ............................................ 39 
Table 5‒5: 
Schedule for PK Sampling (Confirmatory Cohorts) ........................................ 40 
Table 11‒1: 
Mandatory laboratory measurements ............................................................... 78 
Table 11‒2: 
Optional laboratory measurements .................................................................. 78 
Table 11‒3: 
Required investigations and follow-up for PDILI ........................................... 80 
Table 11‒4: 
Recommended PDILI laboratory measurementsa ............................................ 82 
Table 11‒5: 
PDILI information to be collected ................................................................... 83 
 
LIST OF FIGURES 
Figure 5‒1: 
Schematic overview of the study (Exploratory Cohort) .................................. 41 
Figure 5‒2: 
Screening and Evaluation Periods (Exploratory Cohort)................................. 42 
Figure 5‒3: 
Schematic overview of the study (Confirmatory Cohorts) .............................. 43 
Figure 5‒4: 
Screening and Evaluation Periods (Confirmatory Cohorts) ............................ 44 
Figure 11‒1: Adverse event reporting flowchart ................................................................... 74 
 
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LIST OF ABBREVIATIONS 
AE 
adverse event 
AED 
antiepileptic drug 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
area under the curve 
Bayley-III® 
Bayley Scales of Infant and Toddler Development®, Third Edition 
bid 
(bis in die) twice daily 
BRV 
brivaracetam 
BZD 
benzodiazepine 
CDMS 
clinical data management system 
CI 
confidence interval 
CGA 
corrected gestational age 
CNS 
central nervous system 
CPMP 
Committee for Proprietary Medicinal Products 
CRO 
contract research organization 
CTD 
Clinical Trials Directive 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report form 
EEG 
electroencephalogram 
EMA 
European Medicines Agency 
ENS 
electroencephalographic neonatal seizures 
EPV 
Extension Period Visit 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
GA 
gestational age 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HIE 
hypoxic-ischemic encephalopathy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
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IMP 
investigational medicinal product 
IRT 
interactive response technology 
iv 
intravenous(ly) 
LDC 
lidocaine 
LEV 
levetiracetam 
LFT 
liver function test 
MDZ 
midazolam 
N-PASS 
neonatal pain, agitation and sedation scale 
PB 
phenobarbital 
PDCO 
Paediatric Committee 
PDILI 
potential drug-induced liver injury 
PHT 
phenytoin 
PNA 
postnatal age 
PK 
pharmacokinetic 
POS 
partial-onset seizure 
PS 
Patient Safety 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
standard of care 
SOP 
Standard Operating Procedure 
SS 
Safety Set 
SV2A 
synaptic vesicle protein 2A 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
VEEG 
(multichannel) video-electroencephalography 
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1 
SUMMARY 
N01349 is a Phase 2/3, multicenter, open-label, single-arm study to evaluate the 
pharmacokinetics (PK), seizure activity/efficacy (interpreted as “efficacy on seizure activity” and 
referred to as “efficacy” in the protocol), and safety of brivaracetam (BRV) in neonates with 
repeated electroencephalographic (EEG) seizures. Subjects will first receive antiepileptic drugs 
(AEDs) for the treatment of electroencephalographic neonatal seizures (ENS) (first-line, second-
line, or subsequent treatment, which may have started prior to the subject’s admission into the 
study site; dose and dosing regimen at the Investigator’s discretion). If they do not have adequate 
seizure control after the treatment with AEDs, they may be enrolled into N01349. 
As the patient population of neonates with ENS is limited, N01349 is designed with a 2-step 
approach to allow for confirmation (or adjustment) of BRV dosing based on results from the first 
step (Exploratory Cohort) and evaluation of BRV efficacy in the second step (Confirmatory 
Cohorts). This adaptive design allows for the determination of dose and the collection of PK, 
safety, and efficacy data, thereby potentially providing rapid access to alternative treatment in 
neonates.  
For the Exploratory Cohort (first step), enrolled subjects will receive 1 or more of the following 
AEDs prior to or at the time of enrollment: phenobarbital (PB), midazolam (MDZ), phenytoin 
(PHT), levetiracetam (LEV), or lidocaine (LDC) for the treatment of ENS (first-line, second-line, 
or subsequent treatment; choice of treatment, dose, and dosing frequency is at the discretion of 
the Investigator) prior to receiving BRV. Subsequently, an initial low dose of BRV intravenous 
(iv) solution for injection will be administered. At the discretion of the Investigator, 3 additional 
iv BRV doses can be administered, up to a total of 4 iv BRV doses (0.5mg/kg twice daily [bid]), 
during the 48-hour Evaluation Period to determine the PK of BRV in neonates. This treatment 
represents the first use of BRV in neonates (0.5mg/kg bid), which is 4-fold less than the highest 
dosage of 4mg/kg/day that has been used previously in study N01263 (Section 2.2). 
In BRV PK modeling studies CL0187 and N01331, PK profiles were extrapolated allometrically 
to the neonatal age group from the pediatric data collected in N01263 (age range of ≥1 month to 
<16 years). A total of 600 samples from 96 subjects were used for this modeling. The results of 
this modeling suggest that a dosing regimen of 2mg/kg bid in pediatric subjects ≥1 month to <16 
years of age with a maximum of 100mg bid (for patients with a bodyweight of 50kg or more) 
would result in plasma concentration profiles similar to those attained in older children and 
adults who received therapeutic doses of BRV (up to 100mg bid). Since extrapolation of data 
from subjects ≥1 month to subjects ≤2 weeks may be imprecise due to variability in ontogeny in 
the metabolic and excretory functions in neonates, actual PK measurements conducted in the 
Exploratory Cohort of N01349 will be used to confirm the relationship between dose and plasma 
concentration in neonates. 
For the Confirmatory Cohorts (second step with 3 consecutive cohorts planned), the efficacy of 
BRV will be evaluated. Subjects may have received 1 or more of the following AEDs prior to or 
at the time of enrollment: PB, MDZ, LEV (≤60mg/kg/day), PHT, or LDC. The iv dose and 
dosing frequency of BRV selected for the Confirmatory Cohorts will be determined by the 
evaluation of BRV plasma concentrations from the Exploratory Cohort, as well as by the PK 
modeling of N01263 data described above, to be within the range of plasma concentrations 
observed in children ≥1 month old who received BRV 4mg/kg/day. A dosage of BRV 
4mg/kg/day for neonates is predicted to be approximately equivalent to the highest BRV dose 
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(200mg/day) approved as adjunctive therapy for partial-onset seizures (POS) in patients 
≥16 years of age. 
The recommendation to confirm or adjust the originally calculated BRV dose of the 
Confirmatory Cohorts of study N01349 will be given by the Data Monitoring Committee (DMC) 
after review of PK and safety data of the Exploratory Cohort. Based on the DMC meeting held 
on 05 Nov 2020, the BRV dose and frequency selected for the Confirmatory Cohorts is 1mg/kg 
bid (2mg/kg/day). Based on data from the Confirmatory Cohorts, the BRV dose may be further 
adjusted in a staggered approach as determined by the DMC. 
The safety and PK of BRV will be evaluated in all 4 cohorts. At the end of the Evaluation 
Period, subjects from both the Exploratory and Confirmatory Cohorts may enter the BRV 
Extension Period.  
The primary objective of this study is to evaluate the PK of BRV in neonates who have seizures 
that are not adequately controlled with previous AED treatment, and to identify the optimal BRV 
dose (Exploratory Cohort) for the treatment of subjects enrolled into the Confirmatory Cohorts 
of this study. Secondary objectives include the evaluation of the short-term safety and tolerability 
of BRV in neonates and the evaluation of the efficacy of BRV in severe and nonsevere seizure 
burden (defined as total minutes of ENS per hour) in neonates with seizures that are not 
adequately controlled with previous AED treatment. 
This study will enroll at least 42 evaluable subjects (at least 6 subjects in the Exploratory Cohort, 
at least 36 subjects in the Confirmatory Cohorts, including at least 2 subjects undergoing 
hypothermia treatment in the Exploratory Cohort and each of the 3 Confirmatory Cohorts). At 
enrollment, subjects must be at least 34 weeks of corrected gestational age (CGA). In addition, 
term neonates up to 27 days of postnatal age (PNA) and preterm neonates up to 40 weeks of 
CGA and 27 days of PNA can be enrolled. 
Subjects must have a confirmed diagnosis of ENS by multichannel 
video-electroencephalography (VEEG) of ≥2 minutes of cumulative ENS or ≥3 identifiable ENS 
prior to entering the Evaluation Period (ENS is defined as a seizure lasting for at least 10 seconds 
on VEEG), despite receiving AED treatment. The maximum study duration per subject is 
expected to be up to 75 days, which consists of a Screening Period, Baseline Period 
(Confirmatory Cohorts only), Evaluation Period, BRV Extension Period, Down-Titration Period 
(Confirmatory Cohorts only), and Safety Follow-Up Period. There is a possibility that in certain 
regions sites may not be ready to transition subjects to EP0156 at the time enrollment into 
N01266 will be closed. To avoid that enrollment into N01349 must pause from early Sep 2021 
onwards, subjects will then be allowed to stay in N01349 for up to 90 days of PNA until rollover 
to the long-term study is possible. In this event, the maximum study duration for subjects who 
remain in the study for up to 90 days of PNA and do not enter the long-term study will then be 
up to 130 days (90 days of PNA, up to 7 days for the Down-Titration Period, and up to 33 days 
for the Safety Follow-Up Period). All subjects who participate in the BRV Extension Period 
must be offered entry into a long-term study, if they meet the eligibility criteria. Before entering 
the long-term study, subjects must be on oral BRV.  
The PK variables are the plasma concentrations of BRV, the area under the curve (AUC), 
volume of distribution, and clearance of BRV in neonates. Further, PK assessments will include 
plasma concentrations of concomitant PB and/or PHT if administered.  
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The safety variables are adverse events (AEs) as reported by the Investigator, withdrawal and 
rebound phenomena, and mechanical ventilation over the Evaluation Period of the Exploratory 
Cohort and the Confirmatory Cohorts. In addition, safety variables also include the change from 
Baseline to the end of the Evaluation Period for the following variables: vital signs, safety 
laboratory tests, heart rate, physical and neurological examination (Sarnat scale for subjects with 
hypoxic-ischemic encephalopathy [HIE]), psychometric parameters (neonatal pain, agitation, and 
sedation scale [N-PASS]), EEG-parameters, the severity of HIE (Thompson score for subjects 
with HIE); and change from Baseline to the Safety Follow-Up Visit for biometric parameters 
(length, body weight, and head circumference). 
The efficacy of BRV will be analyzed for the Confirmatory Cohorts based on the following 
variables: 
The proportion of responders to BRV treatment from Baseline to 3 hours after the initial BRV 
dose. A BRV responder is defined as a subject who achieves a reduction in seizure burden (ENS 
in minutes per hour), without need for rescue medication, compared to the seizure burden 
measured during the Baseline Period immediately prior to BRV administration, evaluated for a 
2-hour period starting 1 hour after the start of initial BRV treatment. Reduction in seizure burden 
is defined as at least 80% reduction in nonsevere seizure burden (nonsevere seizure burden is 
defined as ≤50% seizure activity on VEEG in all 30-minute timespans) or at least 50% reduction 
in severe seizure burden (severe seizure burden is defined as >50% seizure activity on VEEG in 
any 30-minute timespan). Timespans of 30 minutes refer to the following intervals within the 
2-hour period: 0 to ≤30 minutes, >30 to ≤60 minutes, >60 to ≤90 minutes, and >90 to 
≤120 minutes. 
Secondary efficacy variables will also include the proportion of subjects with at least 
80% reduction in nonsevere seizure burden from Baseline to 3 hours after the initial BRV 
treatment, the proportion of subjects with at least 50% reduction in severe seizure burden from 
Baseline to 3 hours after the initial BRV treatment, the absolute and percentage reduction in 
average seizure burden measured by continuous VEEG from Baseline to the end of the 96-hour 
Evaluation Period, the proportion of BRV responders at the end of the 96-hour Evaluation 
Period, the proportion of subjects who are seizure-free (100% reduction in seizure burden from 
Baseline) at 24 hours following the start of initial BRV treatment, categorized by subjects with 
nonsevere or severe seizure burden at Baseline, the time to reduction in seizure burden for BRV 
responders (defined as the first timepoint when BRV responder criteria are met), seizure freedom 
at the end of the Down-Titration Period, rate of at least 50% reduction in ENS frequency per 
hour from Baseline to the end of the 96-hour Evaluation Period, the proportion of subjects who 
are seizure-free by time interval (at 3 hours, at 3 hour intervals thereafter through 24 hours, and 
every 12 hours to 24 hours following the start of the initial BRV treatment), and the absolute and 
percent difference in clinical seizures at the end of the 24-hour Evaluation Period from Baseline 
for neonates with motor seizures at the time of inclusion. 
Other efficacy variables are the absolute and percentage reduction from Baseline in seizure 
burden at the defined evaluation periods, the categorized percentage reduction from Baseline to 
the end of the 96-hour Evaluation Period in seizure burden, the proportion of BRV responders by 
time interval at the defined evaluation periods, the proportion of subjects who switch over from 
BRV to another AED during the 96-hour Evaluation Period, and the proportion of responders to 
other treatment during the 96-hour Evaluation Period. 
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2 
INTRODUCTION 
2.1 
Epidemiology and treatment of targeted disease 
Seizures occur more often during the neonatal period than at any other time during life (Volpe, 
2008). The most common cause of neonatal seizures is HIE as a result of perinatal asphyxia (van 
Rooij et al, 2013a). A population-based study suggested that 42% of neonatal seizures were 
observed following HIE (van Rooij et al, 2013a). Other causes include intracranial hemorrhage 
and stroke, infections of the central nervous system (CNS), congenital malformations, inborn 
errors of metabolism, transient metabolic disturbances, maternal drug abuse, or rare neonatal 
epilepsy syndromes (benign familial neonatal-infantile seizures or fifth-day seizures) (Volpe, 
2008; Ronen et al, 1999).  
Clinical recognition of seizures in newborns is not always simple due to a highly variable clinical 
expression (Volpe, 2008; Mizrahi and Kellaway, 1987). As demonstrated by prolonged VEEG 
recordings, especially following AED treatments, ENS patterns are not always accompanied by 
clinical signs (Scher et al, 2003; Boylan et al, 2002; Clancy et al, 1988; Mizrahi and Kellaway, 
1987).  
First-generation AEDs, such as PB and PHT, remain the drugs of first (and second) choice 
because of extensive clinical experience, despite their limited clinical effectiveness and potential 
neurotoxicity (van Rooij et al, 2013b). 
In addition to MDZ, other benzodiazepines (BZDs; eg, lorazepam and clonazepam) are used for 
the treatment of neonatal seizures, often in PB-refractory cases. As one of the most lipophilic 
BZDs, MDZ readily crosses the blood-brain barrier and provides the advantage of very rapid 
onset of action. The formation of pharmacologically active (glucuronidated) metabolites of MDZ 
is considered a disadvantage of MDZ use since drug-drug interactions or renal impairment could 
cause an undesired accumulation of these metabolites (van Rooij et al, 2013a).  
Current treatments for neonatal seizure include PB, PHT, LEV, LDC, and MDZ (Slaughter et al, 
2013).  
2.2 
Background information regarding product 
Brivaracetam ((2S)-2-[(4R)-2-oxo-4-propyltetrahydro-1H-pyrrol-1-yl] butanamide) displays a 
high and selective affinity for the synaptic vesicle protein 2A (SV2A) in the brain. Binding to 
SV2A is believed to be the primary mechanism for BRV anticonvulsant activity. Between 2016 
and 2018, marketing authorization for the use of oral and iv BRV as adjunctive treatment for 
POS was granted in the EU, US, Russia, Turkey, Mexico, Australia, India, Argentina, Israel, 
United Arab Emirates, Qatar, Hong Kong, and Korea (film coated tablet, oral solution) for 
patients 16 years of age and older with epilepsy and in Switzerland and Canada for patients 
18 years of age and older with epilepsy. Brivaracetam is approved in the US as monotherapy, 
based on extrapolation, for the treatment of POS in patients with epilepsy aged 16 years and 
older. An application for the extension of indication to the pediatric population from 4 years of 
age in the EU (adjunctive) and the US (adjunctive and monotherapy) based on the concept of 
extrapolation of efficacy data from the adult population was approved in 2018. Of note, in the 
US, BRV injection is indicated for the treatment of POS only in adult patients (16 years of age 
and older).  
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Brivaracetam is weakly bound (≤20%) to plasma proteins. The volume of distribution is 0.5L/kg, 
a value close to that of the total body water. 
Brivaracetam is rapidly and evenly distributed in most tissues and penetrates rapidly into the 
brain. The main metabolic pathway of BRV is by hydrolysis of the acetamide group to the 
corresponding carboxylic acid, ucb-42145, while a second pathway is the ω1-hydroxylation into 
ucb-100406-1 mediated by cytochrome P450 (CYP)2C19. The combination of these 2 pathways 
results in the terminal metabolite (hydroxyacid), ucb-107092-1. These metabolites are not 
pharmacologically active. Brivaracetam is eliminated primarily by metabolism and by excretion 
in the urine. More than 95% of the dose, including metabolites, is excreted in the urine within 
72 hours after dosing in adults. The terminal half-life is approximately 9 hours. 
The first BRV pediatric study was N01263, which is described as follows:  
N01263 was a completed open-label, multicenter, fixed 3-step up-titration, adjunctive therapy 
study of the PK, safety, and efficacy of BRV in subjects ≥1 month old to <16 years of age with 
epilepsy. The study enrolled 100 subjects with either focal or generalized epilepsy. Doses of 
BRV (oral solution) were adjusted by body weight and did not exceed a maximum of 50mg/day, 
100mg/day, and 200mg/day for each titration step.  
A total of 100 subjects were enrolled in N01263: 99 subjects received the study drug and were 
included in the Safety Set (SS). Results from N01263 indicate that BRV was generally 
well-tolerated and that the safety profile in pediatric subjects was consistent with the known 
safety profile in adult subjects. Six subjects discontinued the study due to treatment-emergent 
adverse events (TEAEs), including 1 serious adverse event (SAE) that was moderate in intensity. 
All severe TEAEs and 11 out of 12 treatment-emergent SAEs were considered to be not related 
to study drug by the Investigator. No deaths were reported. The TEAE profile in pediatric 
subjects in this study was consistent with the known BRV safety profile in adults with a low 
incidence of dizziness as the main difference. There was no dose dependency observed in the 
overall incidence of TEAEs. In general, there were no clinically meaningful changes in 
laboratory parameters, vital signs, or electrocardiograms (ECGs). 
Pharmacokinetic analyses performed for N01263 demonstrated that BRV plasma concentrations 
increased with increasing age and increased proportionally to the dose, which was indicated by 
the approximate doubling of trough BRV plasma concentration with every doubling of the BRV 
dose. Trough plasma concentration in the ≥1 month to <2 years age group was approximately 
30% to 45% lower than in adolescents. 
For the 97 subjects included in the efficacy analysis, 47 subjects (58.8%) had a -25% to <25% 
reduction in the number of seizure days from Baseline to the end of the Evaluation Period, and 
26 subjects (32.5% of all subjects) had a ≥25% reduction. Similar observations were made 
overall across age groups and by seizure category. Six subjects (7.5% of all subjects) 
experienced a 100% reduction in the number of seizure days from Baseline to the end of the 
Evaluation Period, and 7 subjects (8.8% of all subjects) experienced a <-25% reduction.  
Overall, 14 subjects (14.4%) experienced seizure freedom over the Evaluation Period, based on 
the Data Record Card data. The number of subjects with seizure freedom was highest in the 
≥2 years to <12 years age group (9 subjects [18.0%]), with a similar number of subjects in the 
≥1 month to <2 years and ≥12 years to <16 years age groups (3 subjects [10.0%] and 2 subjects 
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[11.8%], respectively). The overall mean proportion of seizure-free days was 0.5 days 
(±0.4 days) and was similar regardless of age group or seizure type (range: 0.3 days to 0.7 days).  
N01266, an ongoing, open-label, multicenter study, was designed as a long-term follow-up study 
for subjects who had enrolled in N01263 and the other studies conducted with BRV in the 
pediatric population from birth to 18 years of age. The objectives of this study include evaluation 
of the long-term safety and efficacy of bid administration of BRV oral solution and tablets in 
pediatric subjects with epilepsy; the maximum allowable BRV dosage is 5mg/kg/day, not to 
exceed 200mg/day in subjects with body weights >40kg.  
Based on the results of population PK modeling studies CL00187 and N01331, it was concluded 
that a dosing regimen of 2.0mg/kg bid in pediatric subjects ≥1 month to <16 years of age with a 
maximum of 100mg bid should result in plasma concentration profiles similar to those attained 
in older children and adults who receive therapeutic doses of BRV (up to 200mg per day). 
Extrapolation of the model to neonates suggested that doses of 2mg/kg to 3mg/kg bid might be 
required to achieve exposure similar to adults receiving the maximum dose of 200mg bid. Since 
extrapolation of data from subjects more than 1 month old to subjects 2 weeks of age or younger 
may be imprecise due to variability in ontogeny in the metabolic and excretory functions in 
neonates, actual PK measurements (ie, those conducted in the Exploratory Cohort of N01349) 
are needed to confirm the relationship between dose and plasma concentration in neonates. 
Additional information about BRV, including the current information pertaining to the pediatric 
development program, is provided in the Investigator’s Brochure (IB). 
2.3 
Rationale for the study 
Neonatal seizures are described in the International League Against Epilepsy report as “subtle 
because the manifestations are often overlooked.” Most neonatal seizures do not comply with the 
usual term epilepsy (enduring predisposition to seizures) because they are symptomatic 
(provoked, reactive) seizures most commonly caused by HIE, cerebral infarction, or infection. 
Due to growing evidence that neonatal seizures contribute to an adverse neurodevelopmental 
outcome, physicians are increasingly focused on the diagnosis and treatment of this condition 
(Glass et al, 2012). The current available data from randomized controlled studies to support the 
choice of AEDs for this indication are limited, and there are currently no definite 
recommendations on the most suitable treatment option to use (Pressler and Mangum, 2013; van 
Rooij et al, 2013a). Thus, there is a need to investigate which AEDs should be used to treat 
neonatal seizures and their most appropriate dosages (Pressler and Mangum, 2013; Glass et al, 
2012). Furthermore, although newer AEDs are efficacious for the treatment of seizures in adults 
and older children, limited progress has been made in the treatment of neonatal seizures (Pressler 
et al, 2015; Tulloch et al 2012). Therefore, clinical studies to assess the efficacy and safety of 
new treatment options in neonates are warranted. 
Thus far, BRV is well-tolerated orally up to 200mg/day in adult subjects with epilepsy and in 
children 1 month old to 16 years of age receiving up to 4mg/kg/day. Intravenously administered 
BRV is bioequivalent to the same dosage given orally in healthy adults when given as a bolus or 
as a 15-minute infusion. Results have shown that a single iv BRV dose of up to 150mg as a 
15-minute infusion or as a bolus dose is well-tolerated in adults. Based on these results, the iv 
route of administration and the proposed dosages to be used in N01349 are justified. 
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N01349 represents the first study of BRV in neonatal subjects, and will evaluate the PK, 
efficacy, and safety of BRV in neonates (up to 27 days of PNA and preterm neonates up to 
40 weeks of CGA and 27 days of PNA). 
3 
STUDY OBJECTIVES 
3.1 
Primary objective 
The primary objective is to evaluate the PK of BRV in neonates who have seizures that are not 
adequately controlled with previous AED treatment, and to identify the optimal BRV dose 
(Exploratory Cohort) for the treatment of subjects enrolled into the Confirmatory Cohorts of this 
study. 
3.2 
Secondary objectives 
The secondary objectives are: 
• To evaluate the efficacy of BRV in severe and nonsevere seizure burden (defined as total 
minutes of ENS per hour) in neonates with seizures that are not adequately controlled with 
previous AED treatment 
• To evaluate the short-term safety and tolerability of BRV in neonates 
4 
STUDY VARIABLES 
4.1 
PK variables (Exploratory and Confirmatory Cohorts) 
4.1.1 
Primary PK variable 
The primary PK variable is as follows: 
• Plasma concentrations of BRV following first dose on Day 1 
4.1.2 
Other PK variables 
• Plasma concentrations of BRV on other occasions 
• Plasma concentrations of BRV metabolites ucb-42145 (acid), ucb-100406-1 (hydroxy), and 
ucb-107092-1 (hydroxyacid) 
• AUC, volume of distribution, and clearance of BRV 
• Plasma concentrations of concomitant AEDs if administered  
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4.2 
Efficacy variables (Confirmatory Cohorts only) 
The variables for the evaluation of BRV efficacy are described in Section 4.2.1 (Secondary 
efficacy variables) and Section 4.2.2 (Other efficacy variables). 
4.2.1 
Secondary efficacy variables 
The main secondary efficacy variable is as follows: 
• Proportion of responders to BRV treatment from Baseline to 3 hours after the initial BRV 
dose 
A BRV responder is defined as a subject who achieves the following reduction in seizure 
burden (ENS in minutes per hour) without need for rescue medication, compared to the 
seizure burden measured during the Baseline Period immediately prior to BRV 
administration, evaluated for a 2-hour period starting 1 hour after the start of initial BRV 
treatment: 
− At least 80% reduction in nonsevere seizure burden 
(Nonsevere seizure burden is defined as ≤50% seizure activity on VEEG in all 30-minute 
timespans) 
OR 
− At least 50% reduction in severe seizure burden 
(Severe seizure burden is defined as >50% seizure activity on VEEG in any 30-minute 
timespan).  Timespans of 30 minutes refer to the following intervals within the 2-hour period: 0 
to ≤30 minutes, >30 to ≤60 minutes, >60 to ≤90 minutes, and >90 to ≤120 minutes. 
For this study, an ENS is defined as an EEG seizure lasting for at least 10 seconds on VEEG. 
Baseline seizure burden is defined as seizure burden measured on the continuous VEEG (total 
ENS in minutes per hour) during a period of up to 1 hour immediately prior to the first 
administration of study drug.  
In addition, the secondary efficacy variables will include: 
• Proportion of subjects with at least 80% reduction in nonsevere seizure burden from Baseline 
to 3 hours after the initial BRV treatment 
• Proportion of subjects with at least 50% reduction in severe seizure burden from Baseline to 
3 hours after the initial BRV treatment 
• Absolute reduction in average seizure burden measured by continuous VEEG from Baseline 
to the end of the 96-hour Evaluation Period 
• Percent reduction in average seizure burden measured by continuous VEEG from Baseline to 
the end of the 96-hour Evaluation Period 
• Proportion of BRV responders at the end of the 96-hour Evaluation Period  
• Proportion of subjects who are seizure-free (100% reduction in seizure burden from 
Baseline) at 24 hours following the start of initial BRV treatment, categorized by subjects 
with nonsevere or severe seizure burden at Baseline  
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• Time to reduction in seizure burden for BRV responders (defined as the first timepoint when 
BRV responder criteria are met) 
• Seizure freedom at the end of the Down-Titration Period  
• Rate of at least 50% reduction in ENS frequency per hour from Baseline to the end of the 
96-hour Evaluation Period 
• Proportion of subjects who are seizure-free by time interval at 3 hours, at 3-hour intervals 
thereafter through 24 hours, and every 12 hours to 24 hours thereafter up until the end of the 
96-hour Evaluation Period following the start of the initial BRV treatment 
• Absolute difference in clinical seizures at the end of the 24-hour Evaluation Period from 
Baseline for neonates with motor seizures at the time of inclusion 
• Percent difference in clinical seizures at the end of the 24-hour Evaluation Period from 
Baseline for neonates with motor seizures at the time of inclusion 
The use of rescue medication will affect the analysis of the main secondary efficacy variable(see 
Section 13.5.1). The factors affecting the definition of BRV responders for the analysis of the 
secondary efficacy variables are described in Section 10.1. 
4.2.2 
Other efficacy variables 
Other efficacy variables will include: 
• Absolute reduction from Baseline in seizure burden at evaluation periods of 0 hours to 
3 hours, >3 hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, >24 hours to 
36 hours, >36 hours to 48 hours, >48 hours to 72 hours, and >72 hours to 96 hours after the 
start of initial BRV treatment 
• Percent reduction from Baseline in seizure burden at evaluation periods of 0 hours to 3 hours, 
>3 hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, >24 hours to 36 hours, 
>36 hours to 48 hours, >48 hours to 72 hours, and >72 hours to 96 hours after the start of 
initial BRV treatment 
• Categorized percentage reduction from Baseline to the end of the 96-hour Evaluation Period 
in seizure burden (<-25% [worsening], -25% to <25% [no change], 25% to <50%, 50% to 
<80%, and ≥80%)  
• Proportion of BRV responders by time interval at evaluation periods of 0 hours to 3 hours, 
>3 hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, >24 hours to 36 hours, 
>36 hours to 48 hours, >48 hours to 72 hours, and >72 hours to 96 hours after the start of 
initial BRV treatment 
• Proportion of subjects who switch over from BRV to another AED during the 96-hour 
Evaluation Period 
• Proportion of responders to other treatment during the 96-hour Evaluation Period (including 
at the end of the 96-hour Evaluation Period, and by time intervals: 0 hours to 3 hours, 
>3 hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, >24 hours to 36 hours, 
>36 hours to 48 hours, >48 hours to 72 hours, and >72 hours to 96 hours after the start of 
initial BRV treatment)  
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(A responder to other treatment is defined as at least 80% reduction in nonsevere seizure 
burden from start of other treatment to end of other treatment or at least 50% reduction in 
severe seizure burden from the initiation of other treatment to end of other treatment during 
the 96-hour Evaluation Period). 
4.3 
Safety variables (Exploratory and Confirmatory Cohorts) 
4.3.1 
Secondary safety variable  
The secondary safety variable is as follows: 
• AEs as reported by the Investigator 
4.3.2 
Other safety variables 
• Change from Baseline in vital signs (blood pressure, heart rate, respiratory rate [including 
apneas], oxygen saturation [pulse oximetry], and body temperature)  
• Change from Baseline in safety laboratory tests to the end of the Evaluation Period 
• Change from Baseline in heart rate at 3 hours, 24 hours, 48 hours, and 96 hours after the start 
of initial BRV treatment  
• Change from Baseline in physical and neurological examination 24 hours, 48 hours, 
72 hours, and 96 hours after the start of initial BRV treatment (Sarnat scale; for subjects with 
HIE only) 
• Change from Baseline in EEG-parameters (assessment of sedation) to the end of the 
Evaluation Period (Confirmatory Cohorts only)  
• Change from Baseline in severity of HIE to the end of the Evaluation Period (Thompson 
score; for subjects with HIE only) 
• Change from Baseline in N-PASS score (neonatal pain and agitation measures) to the end of 
the Evaluation Period 
• Change from Baseline in biometric parameters at the Safety Follow-Up Visit: length, body 
weight, and head circumference (head circumference Baseline measurement should be taken 
within 7 days prior to drug administration, or at birth for subjects ≤7 days old)  
• Withdrawal and rebound phenomena  
• Mechanical ventilation: 
− Number and percentage of subjects requiring mechanical ventilation during the 
Evaluation Period 
− Duration of mechanical ventilation during the Evaluation Period 
Neurodevelopmental tests validated for age and language will be done after 1 year for subjects 
who enter the long-term follow-up study in countries where a validated translation of the Bayley 
Scales of Infant and Toddler Development®, Third Edition (Bayley-III®) score is available. 
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5 
STUDY DESIGN 
5.1 
Study description 
N01349 is a Phase 2/3, multicenter, open-label, single-arm study to evaluate the PK, efficacy, 
and safety of BRV in neonates with repeated EEG seizures.  
N01349 consists of a 2-step design and includes a descriptive comparison with a historical 
control group (matched in age and condition) from literature treated with AEDs per SOC and 
diagnostic methods. 
For the Exploratory Cohort (first step), enrolled subjects will have received 1 or more of 
following AEDs prior to or at the time of enrollment: PB, MDZ, PHT, LEV, or LDC for the 
treatment of ENS (first-line, second-line, or subsequent treatment; choice of treatment, dose, and 
dosing frequency are at the discretion of the Investigator) prior to receiving BRV. Subsequently, 
a low dose of BRV iv solution for injection will be administered. At the discretion of the 
Investigator, 3 additional iv BRV doses, up to a total of 4 iv BRV doses (0.5mg/kg bid), can be 
administered during the 48-hour Evaluation Period. This treatment, which is the first use of BRV 
in neonates, is 4-fold less than the highest dose of 4mg/kg/day dosage (2mg/kg bid) that has been 
used previously in infants ≥1 month old.  
For the Confirmatory Cohorts (second step), 3 consecutive cohorts are planned, and the efficacy 
of BRV will be evaluated. Subjects may receive 1 or more of the following AEDs prior to or at 
the time of enrollment: PB, MDZ, PHT, LEV (≤60mg/kg.day), PHT, or LDC. The iv dose of 
BRV selected for the Confirmatory Cohorts will be determined by the evaluation of BRV plasma 
concentrations from the Exploratory Cohort, as well as by previous PK modeling of N01263 
data, to be within the range of plasma concentrations observed in children ≥1 month old who 
received 4mg/kg/day. A dosage of BRV 4mg/kg/day for neonates is predicted to be 
approximately equivalent to the highest BRV dosage (200mg/day) that has been studied in the 
adult Phase 3 program (eg, N01358 and N01258).  
The PK and safety of BRV will be evaluated in all cohorts. The recommendation to confirm or 
adjust the originally calculated BRV dose of the Confirmatory Cohorts of study N01349 will be 
given by the DMC after review of PK and safety data of the Exploratory Cohort. Based on the 
DMC meeting held on 05 Nov 2020, the BRV dose and frequency selected for the Confirmatory 
Cohorts is 1mg/kg bid (2mg/kg/day). Based on data from the Confirmatory Cohorts, the BRV 
dose may be further adjusted in a staggered approach as determined by the DMC. 
At the end of the Evaluation Period, subjects from both the Exploratory and Confirmatory 
Cohorts may enter the BRV Extension Period. 
All subjects who participate in the BRV Extension Period must be offered entry into a long-term 
study, if they meet the eligibility criteria. Before entering the long-term study, subjects must be 
on oral BRV.  
Blood samples for routine assay of hematology, biochemistry, liver enzymes, and endocrinology 
will be collected in line with Section 13.2 of the “Ethical Considerations for Clinical Trials on 
Medicinal Products Conducted with the Paediatric Population” (European Union Commission ad 
hoc group, 2008), and according to the schedule of study assessments in Table 5‒1 (Exploratory 
Cohort) and Table 5‒2 (Confirmatory Cohorts). The local laboratories will perform the routine 
analysis of blood samples. For Screening and determination of eligibility, use of laboratory data 
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acquired prior to Screening per standard of care inside or outside the study site within 36 hours 
prior to the start of the Evaluation Period is allowed.    
Interpretation of VEEGs recorded for the Confirmatory Cohorts will be done by local readers but 
may be supported by the blinded central reader, as needed. Start and stop of BRV treatment and 
the administration of rescue medication or alternative AEDs will be digitally marked as 
treatment events on VEEGs. The VEEG recordings will subsequently be evaluated by a blinded, 
independent central reader at the end of the study. The independent central reader will be blinded 
from site-specific information and the subject’s medical history.  
Subjects assigned to the Confirmatory Cohorts will be evaluated with VEEG monitoring at least 
during the Baseline, Evaluation, and Down-Titration Period. Interruption of the VEEG is 
allowed up to 30 minutes per day. Depending on medical needs related to SOC (eg, MRIs to be 
performed), interruptions longer than this are acceptable. However, every effort should be made 
to avoid VEEG interruption of the Baseline VEEG and during the first 3 hours after the start of 
the initial BRV administration. The video portion of the VEEG monitoring will assist 
Investigators in accurately diagnosing ENS and distinguishing artifacts from epileptiform 
discharges/seizures. 
For subjects undergoing therapeutic hypothermia treatment, the target low body temperature 
achieved and age since birth when cooling began will be recorded. Rewarming of subjects will 
be documented in the same way. 
If appropriate (in the event of screening failures), re-screening will be allowed for the study. 
Re-screening for screen-failed subjects will be allowed with prior consultation of the Medical 
Monitor whenever feasible. Subjects can be re-screened only once. Once a subject has received 
at least one dose of BRV or has left the study because a “must withdrawal” criterion is met, 
re-screening will no longer be possible. 
A continuous consent process will be followed. Parent(s) or legal representative(s) will be 
informed about the study as early as possible and asked to sign the Informed Consent form (ICF) 
after the occurrence of seizures has been confirmed by VEEG; subjects will then be considered 
to be enrolled. During the course of the study, parent(s) or legal representative(s) will be updated 
about the care of their neonate, and continuous consent will be ensured by meetings between the 
Investigator (or designee) and the subject’s parent(s) or legal representative(s). Parent(s) or legal 
representative(s) will not be asked to re-sign and re-date the ICF, but they will be informed that 
they can withdraw their neonate from the study at any time and that this decision will not affect 
the care of their neonate. Continuous consent will be documented in the subjects’ medical charts 
and electronic Case Report form (eCRF). 
A DMC will be in place for the duration of this study. The DMC will meet after completion of 
the 6 subjects in the Exploratory Cohort and after completion of each of the 3 Confirmatory 
Cohorts (12 subjects each). Although it was planned that the DMC will meet at no longer than 
6-month intervals between meetings, due to the low enrollment rate observed, the intervals 
between meetings may be increased per the discretion of the DMC. 
The schedules of assessments during the Screening and Evaluation Periods for the Exploratory 
and Confirmatory Cohorts are presented in Table 5‒1 and Table 5‒2, respectively. The schedule 
of assessments during the BRV Extension, Down-Titration (Confirmatory Cohorts only), and 
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Safety Follow-Up Periods for both the Exploratory and Confirmatory Cohorts are presented in 
Table 5-3. 
Details of the study periods for the Exploratory and Confirmatory Cohorts are described in 
Section 5.1.1 and Section 5.1.2, respectively. 
5.1.1 
Exploratory Cohort 
For the Exploratory Cohort, at least 6 subjects who do not have adequate seizure control after 
they received 1 or more of the following AEDs: PB, MDZ, PHT, LEV, or LDC prior to or at the 
time of enrollment for the treatment of ENS (first-line, second-line, or subsequent treatment, 
which may have started prior to the subject’s admission into the study site; choice of treatment, 
dose, and dosing regimen at the Investigator’s discretion) will be enrolled. The AED treatment 
per SOC can be continued when BRV dosing is initiated. Alternatively, another AED treatment 
(choice of treatment, dose, and dosing regimen at the Investigator´s discretion) must be initiated 
and continue in parallel with BRV treatment. 
At any time after AED treatment per SOC for the treatment of ENS (first-line, second-line, or 
subsequent treatment) was initiated, an initial low dose of BRV (0.5mg/kg [bid]) will be 
administered at the Investigator´s discretion. After the Exploratory Cohort completes the study, a 
PK and safety data review will be performed by the DMC. During the review of data from the 
Exploratory Cohort, the enrollment of subjects will be on hold. 
At least 2 subjects undergoing hypothermia treatment will be included. Subjects in the 
Exploratory Cohort might be replaced due to lack of data, as deemed necessary following the 
review of PK and safety data by the DMC. 
The study periods for the Exploratory Cohort are as follows: 
• Screening Period: from signing and dating of the written ICF up to initiation of the first BRV 
dose. 
The Screening Period starts up to 36 hours prior to the first administration of BRV. 
Phenobarbital, MDZ, PHT, LEV, or LDC may have been administered prior to the subject’s 
enrollment into the study and/or at a location other than the study site. 
Subjects will enter the Evaluation Period and start BRV treatment as soon as the occurrence 
of ENS per inclusion criterion 2a is confirmed by the Investigator based on local EEG. If 
preferred by the Investigator, the central VEEG reader can be consulted to confirm the 
required ENS. 
• Evaluation Period (48 hours): The first BRV infusion marks the starting point of the 
Evaluation Period. At any time after AED treatment per SOC for the treatment of ENS 
(first-line, second-line, or subsequent treatment) was initiated, a low dose of BRV (0.5mg/kg) 
will be administered as an approximately 15-minute iv infusion; additional 3 doses of 
BRV(0.5mg/kg) can be administered every 12 hours for 48 hours (at the discretion of the 
Investigator). The AED treatment per SOC can be continued when BRV dosing is initiated. 
Otherwise, another AED treatment (choice of treatment, dose, and dosing regimen at the 
Investigator´s discretion) must be initiated and continue in parallel with BRV treatment.  
Following the first BRV infusion, 3 to 6 PK blood microsamples (60µL/sample) will be 
collected during the 48-hour Evaluation Period from each subject for the determination of 
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plasma concentrations of BRV and its metabolites, as described in Table 5‒4. The first set of 
3 PK samples will be collected on the first day within specific timeframes (Table 5‒4), with 
the second set of 3 PK samples to be collected within the same timeframes on the second day 
of the 48-hour Evaluation Period. In addition, opportunistic blood samples for the PK 
analysis may be used at the Investigator’s discretion at any time during the Evaluation Period 
(see Section 9.1). Blood for PK samples should be drawn from a line different to that of the 
BRV infusion. The AED PK sample should be collected 3 hours after the start of the initial 
BRV administration. The number of subjects in the Exploratory Cohort may be increased, if 
deemed necessary following the analysis of PK data. 
At the end of the Evaluation Period, subjects who benefit from BRV treatment may enter the 
BRV Extension Period in accordance with the Investigator’s opinion. Subjects not entering 
the BRV Extension Period will proceed immediately to the Safety Follow-Up Period (a visit 
will occur 30±3 days after the final BRV administration). 
• BRV Extension Period (up to 28 days of postnatal age [+7 days]): Subjects can proceed to 
the BRV Extension Period if they benefit from BRV treatment during the Evaluation Period, 
in accordance with the Investigator’s opinion. All subjects who participate in the BRV 
Extension Period must be offered entry into the long-term study, if they meet the eligibility 
criteria. Subjects will participate in the BRV Extension Period until they reach a stable 
condition that will allow them to enter the long-term study. The anticipated duration of the 
BRV Extension Period per subject is up to 28 days of postnatal age (+7 days). Subjects must 
switch to BRV oral solution before entering the long-term study. The timing of the switch 
from iv to oral solution will be at the discretion of the Investigator; subjects who are not able 
to be dosed with BRV oral solution when they reach 28 days of postnatal age may continue 
in the BRV Extension Period for an additional 7 days; subjects who are not able to be 
switched to BRV oral solution by the end of the additional 7 days of the BRV Extension 
Period will not be eligible for enrollment in the long-term study. 
During the BRV Extension Period, subjects may continue receiving the same BRV dose 
administered at the end of the Evaluation Period (ie, BRV 0.5mg/kg bid); the BRV dose 
should not be increased but may be decreased at the discretion of the Investigator.  
• Safety Follow-Up Period: Subjects will proceed to the Safety Follow-Up Period if they do 
not enter the BRV Extension Period. The visit will occur 30±3 days after the final 
administration of BRV. 
5.1.2 
Confirmatory Cohorts 
For the Confirmatory Cohorts, enrollment will only start after the dosing of BRV is determined 
based on the PK findings of the Exploratory Cohort and an existing PK model from N01263. A 
total of at least 36 subjects without adequate seizure control after receiving one or more of the 
following AEDs prior to or at the time of enrollment: PB, MDZ, PHT, LEV (≤60mg/kg/day), or 
LDC (first-line, second-line, or subsequent treatment, which may have started prior to the 
subject’s admission into the study site; dose and dosing regimen at the Investigator’s discretion) 
will enter the Confirmatory Cohorts. The AED treatment can be continued if the subject is on a 
stable dose for at least 1 hour at the time the first BRV infusion is initiated.  
Three consecutive Confirmatory Cohorts (n=12 each) are planned; each cohort must have at least 
2 subjects undergoing hypothermia treatment. A PK and safety data review will be performed by 
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the DMC after completion of each of the 3 Confirmatory Cohorts. Based on the DMC meeting 
held on 05 Nov 2020, the BRV dose and frequency selected for the Confirmatory Cohorts 
is 1mg/kg bid (2mg/kg/day). Based on data from the Confirmatory Cohorts, the BRV dose may 
be further adjusted in a staggered approach as determined by the DMC. During the PK and safety 
data review of data from the first and second Confirmatory Cohorts, the recruitment of subjects 
into subsequent cohorts will continue. 
The study periods for the Confirmatory Cohorts are as follows: 
Screening Period: from signing and dating of the written ICF up to initiation of the first BRV 
dose. 
• The Screening Period starts up to 36 hours prior to the first administration of BRV. 
Phenobarbital, MDZ, PHT, LEV (≤ 60mg/kg/day), or LDC may have been administered 
prior to the subject’s enrollment into the study and/or at a location other than the study 
site. 
• Baseline Period (included in the Screening Period):  
o For subjects with intermittent ENS: at least 1 hour prior to entering the Evaluation 
Period  
o For subjects in status epilepticus: up to 30 minutes prior to entering the Evaluation 
Period. At least 15 minutes of continuous seizures, or 50% of cumulative seizure 
activity during a 30-minute interval are to be confirmed on EEG before the 
administration of BRV can start. 
As soon as subjects are considered to be in status epilepticus, steps required for the 
preparation of the initial BRV infusion can be initiated (eg, assignment of BRV kits 
through interactive response technology [IRT] and the dilution of BRV solution for 
iv infusion), even if the required EEG recording is not completed by that time.  
Status epilepticus in neonates for the purpose of this study is defined as follows: 
• 15 minutes of continuous or cumulative electrographic or electroclinical 
seizure within 30 minutes 
The occurrence of ENS during the Baseline Period must be confirmed either by the 
local or central VEEG reader prior to BRV administration. Preferably, the central 
VEEG reader should confirm the required ENS. Video-EEGs that are acquired per 
standard of care prior to consenting and meet study-specific technical and quality 
requirements (eg, ability for immediate cloud-based central review) can be used as 
part of the Baseline assessment VEEG.  
• Evaluation Period (96 hours): The first administration of BRV marks the starting point of the 
Evaluation Period. Subjects in the Confirmatory Cohorts will receive iv BRV 1mg/kg bid 
(2mg/kg/day), as recommended by the DMC on 05 Nov 2020 based on the results of the PK 
analysis of the Exploratory Cohort as well an existing PK model from N01263. The DMC 
will continue to monitor the PK and safety of the subjects and dosing may be adjusted as new 
data are available. If subjects do not benefit from BRV treatment after 96 hours of BRV 
administration, BRV administration will be stopped and replaced by another AED. 
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Following the first BRV infusion, 6 PK blood microsamples (60µL/sample) will be collected 
during the 96-hour Evaluation Period for each subject for the determination of plasma 
concentrations of BRV and its metabolites, as described in Table 5‒5. Blood for PK samples 
should be drawn from a line different to that of the BRV infusion. 
The AED PK sample should be collected 3 hours after the start of the initial BRV 
administration. In addition, opportunistic blood samples for the PK analysis may be used at 
the Investigator’s discretion at any time during the Evaluation Period (see Section 9.1). 
At the end of the Evaluation Period, subjects who benefit from BRV treatment may enter the 
BRV Extension Period in accordance with the Investigator’s opinion. Subjects not entering 
the BRV Extension Period will proceed to the Down-Titration Period.  
• BRV Extension Period (28 days [up to 90 days] of PNA): Subjects can proceed to the BRV 
Extension Period if they benefit from BRV treatment during the Evaluation Period, in 
accordance with the Investigator’s opinion. All subjects who participate in the BRV 
Extension Period must be offered entry into the long-term study, if they meet the eligibility 
criteria. Subjects will participate in the BRV Extension Period until they reach a stable 
condition that will allow them to enter the long-term study, if epilepsy is confirmed.  
The anticipated duration of the BRV Extension Period per subject is up to 28 (+7) days of 
PNA. Subjects who are not able to be dosed with BRV oral solution at a PNA of 28 days may 
continue in the BRV Extension Period for an additional 7 days; subjects who are not able to 
be switched to BRV oral solution by the end of the additional 7 days of the BRV Extension 
Period will not be eligible for enrollment in the long-term study. 
In the event that a long-term study is temporarily not available, subjects are allowed to 
remain in the BRV Extension Period until they reach a PNA of up to 90 days. For those 
subjects, the assessments planned for Unscheduled Visits (see Section 8.1.3.3) will be 
conducted in intervals of approximately 30 days during the prolonged Extension Period. The 
treatment with BRV will be managed through IVRS. Before subjects can roll-over to the 
long-term study, they must have switched to BRV oral solution.  
• Subjects must switch to BRV oral solution before entering the long-term study. The 
timepoint of the switch from iv to oral solution will be at the discretion of the Investigator.  
During the BRV Extension Period, subjects may continue receiving the same BRV dose 
administered at the end of the Evaluation Period; the BRV dose should not be increased, but 
may be decreased at the discretion of the Investigator.  
Down-Titration Period (up to 1 week): A Down-Titration Period of up to 1 week is 
recommended for subjects in the Confirmatory Cohorts who discontinue BRV treatment 
prior to completion of the Evaluation Period, who do not proceed to the BRV Extension 
Period, or start the BRV Extension Period but do not enter the long-term study. The 
Down-Titration steps and duration may be adjusted at the Investigator’s discretion. 
• Safety Follow-Up Period: Subjects will proceed to the Safety Follow-Up Period once they 
complete the Down-Titration Period. The visit will occur 30±3 days after the final 
administration of BRV. 
Rescue medication should be given if the following occurs:  
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• There is no improvement in seizure burden within the first 3 hours after administration of 
BRV. 
• Seizure burden is unacceptable to the Investigator, in which case rescue medication can be 
given earlier at any time, but ideally not in the first 3 hours after the initial administration of 
BRV.  
Subjects in the Confirmatory Cohorts are allowed to switch over from BRV to another AED (eg, 
MDZ or PHT), if needed. Subjects discontinuing BRV treatment during the Evaluation Period 
should start the Down-Titration Period while completing the Evaluation Period in parallel for the 
full 96 hours. In this case, subjects will complete all study assessments, except the collection of 
blood microsamples for the determination of BRV plasma concentrations. Ideally, changing or 
adding a new treatment should not occur during the first 3 hours after the initial administration of 
BRV. Subjects who are switched from BRV to another AED will not be eligible to participate 
either in the BRV Extension Period or the long-term study.  
5.1.3 
Study duration per subject 
The maximum study duration per subject is expected to be up to 75 days (Screening Period 
[including Baseline Period (Confirmatory Cohorts only)], Evaluation Period, BRV Extension 
Period, Down-Titration Period [Confirmatory Cohorts only], and Safety Follow-Up Period). In 
the event that a long-term study is not available at the time of a subject’s planned transition, the 
maximum study duration for subjects who remain in the study for up to 90 days of PNA and do 
not enter the long-term study will then be up to 130 days (90 days of PNA, up to 1 week for the 
Down-Titration Period, and up to 33 days for the Safety Follow-Up Period). The individual study 
duration will be shorter depending on the type of cohort to which subjects will be assigned, the 
age at enrollment, and the decision to enter the BRV Extension Period.  
The maximum BRV exposure per subject is expected to be up to 42  days, which comprises up to 
4 days during the Evaluation Period (depending on type of cohort), up to 28 (+7) days of PNA 
during the BRV Extension Period, and up to 1 week during the Down-Titration Period for 
subjects in the Confirmatory Cohorts only. For subjects who remain in the study for up to 
90 days of PNA and do not enter the long-term study, maximum BRV exposure per subject is 
expected to be up to 97 days (up to 90 days of PNA and up to 1 week for the Down-Titration 
Period). 
All subjects who do not continue into the long-term study will proceed to the Safety Follow-Up 
Period, and a visit will occur 30±3 days after the final dose of BRV. 
The end of the study is defined as the date of the last visit of the last subject in the study. 
5.1.4 
Planned number of subjects and sites 
At least 42 evaluable subjects will be enrolled in this study, with at least 6 subjects in the 
Exploratory Cohort evaluable for the determination of BRV plasma concentrations and at least 
36 subjects with evaluable PK data in the Confirmatory Cohorts (at least 12 subjects in each of 
the 3 Confirmatory Cohorts). At least 2 subjects undergoing hypothermia treatment will be 
included in the Exploratory Cohort and each of the 3 Confirmatory Cohorts. 
The number of subjects in the Exploratory Cohorts might be increased, if deemed necessary, 
following the analysis of PK data. 
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5.1.5 
Anticipated regions and countries 
Only sites in Europe are planned. 
5.2 
Schedule of study assessments 
The schedules of study assessments during the Screening and Evaluation Periods for the 
Exploratory and Confirmatory Cohorts are presented in Table 5‒1 and Table 5‒2, respectively. 
The PK sampling will be performed according to the schedule provided in Table 5‒4 for the 
Exploratory Cohort and in Table 5‒5 for each Confirmatory Cohort. 
The schedule of study assessments during the BRV Extension, Down-Titration (Confirmatory 
Cohorts only), and Safety Follow-Up Periods are presented in Table 5-3. 
 
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Table 5‒1: 
Schedule of study assessments – Screening and Evaluation Periods (Exploratory Cohort) 
Assessments 
Screening Perioda 
Evaluation Period 
Up to 36h 
-36h 
to 0h  
Timepoint immediately 
before first BRV 
administration 
BRV 
0h 
1h 
2h 
3h 
4h 
6h 
8h 
10h 
12h 
24h 
27h 
34h 
36h 
48h 
(Assessment window) 
- 
- 
- 
(±15min) 
(±30min) 
Informed consentb 
X 
 
-X- 
Subject identification card dispensing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
Xc 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history including Apgar score 
and HIE 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
 
X 
X 
 
 
X 
 
X 
 
 
X 
X 
 
 
 
X 
Physical and neurological examination: 
Sarnat scale for subjects with HIE 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Length 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weightd 
X 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
Head circumferencee 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary cause of seizure 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Psychometric parameters:  
N-PASS and EEG-parameters 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AED treatment (PB, MDZ, PHT, LEV, 
or LDC) 
Xj 
-X - 
Cohort Assignment 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
BRV infusion 
 
 
X 
 
 
 
 
 
 
 
X 
X 
 
 
X 
 
Heart rate monitoring 
 
X 
 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
BRV PK samplesf 
 
 
Xg 
 
X 
 
X 
X 
X 
X 
 
 
AED PK sample (only when PB and 
PHT are used) 
 
 
 
 
X 
 
 
 
 
 
 
 
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Table 5‒1: 
Schedule of study assessments – Screening and Evaluation Periods (Exploratory Cohort) 
Assessments 
Screening Perioda 
Evaluation Period 
Up to 36h 
-36h 
to 0h  
Timepoint immediately 
before first BRV 
administration 
BRV 
0h 
1h 
2h 
3h 
4h 
6h 
8h 
10h 
12h 
24h 
27h 
34h 
36h 
48h 
(Assessment window) 
- 
- 
- 
(±15min) 
(±30min) 
Laboratory assessments (safety) 
 
Xh 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Thompson scorei 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Mechanical ventilation 
 
-X- 
AE(s) 
-X- 
Concomitant medications 
-X- 
Medical procedures 
-X- 
Infusion site reaction monitoringk 
 
 
X 
X 
X 
X 
 
X 
 
 
X 
X 
 
 
X 
X 
Dispense BRV dosing diary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xl 
Dispense BRV for the BRV Extension 
Periodm 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AE(s)=adverse event(s); AED(s)=antiepileptic drug(s); BRV=brivaracetam; BZD(s)=benzodiazepine(s); COVID-19=coronavirus disease 2019; 
ENS=electroencephalographic neonatal seizures; HIE=hypoxic-ischemic encephalopathy; ICF=Informed Consent form; LDC=lidocaine; 
LEV=levetiracetam; MDZ=midazolam; N-PASS=neonatal pain, agitation, and sedation scale; PB=phenobarbital; PHT=phenytoin; PK=pharmacokinetic(s); 
SOC=standard of care 
a Screening Period is from signing and dating of the written ICF up to initiation of the first BRV dose. 
b Parent(s) or legal representative(s) will be informed about the study as early as possible and asked to sign the informed consent after the occurrence of 
seizures is confirmed on local VEEG. Continuous consent will be ensured by meetings between the Investigator (or designee) and the subject’s parent(s) or 
legal representative(s), during the conduct of the study. 
c The occurrence of ENS prior to entering the Evaluation Period must be confirmed by the local VEEG reader prior to initial BRV administration.  
d Measurement of body weight is mandatory prior to BRV treatment and optional at 24 and 48 hours. Dosage of BRV during the Evaluation Period will be 
based on the subject’s weight measured prior to the start of the first BRV administration. However, dosage calculation can be adjusted to a more recent 
weight measurement, upon discretion of the Investigator, if weight is measured during the Evaluation Period.  
e Head circumference Baseline measurement should be taken within 7 days prior to drug administration, or at birth for subjects ≤7 days old. 
f Following the first BRV infusion, 3 to 6 blood microsamples (60µL/sample) will be collected from each subject in the Exploratory Cohort. 
g The schedule of PK sampling for the Exploratory Cohort is also provided in Table 5‒4. 
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Table 5‒1: 
Schedule of study assessments – Screening and Evaluation Periods (Exploratory Cohort) 
Assessments 
Screening Perioda 
Evaluation Period 
Up to 36h 
-36h 
to 0h  
Timepoint immediately 
before first BRV 
administration 
BRV 
0h 
1h 
2h 
3h 
4h 
6h 
8h 
10h 
12h 
24h 
27h 
34h 
36h 
48h 
(Assessment window) 
- 
- 
- 
(±15min) 
(±30min) 
h For Screening and determination of eligibility, use of laboratory data acquired prior to Screening per standard of care inside or outside the study site within 
36 hours prior to the start of the Evaluation Period is allowed.    
i Thompson score will be used to measure the severity of HIE for subjects with HIE. 
j The recording of AEDs will include BZDs and opiates taken by the mother at the time of delivery. In addition, details regarding COVID-19 vaccination will 
be recorded as concomitant medication if the mother was pregnant or breastfeeding when vaccinated.  
k Monitoring for BRV infusion site reactions should take place during and 30 minutes after the end of the infusion. 
l The BRV dosing diary will be dispensed only if the subject enters the BRV Extension Period. 
m Dispensing of BRV is only applicable if the subject enters the BRV Extension Period. 
 
Table 5‒2: 
Schedule of study assessments – Screening and Evaluation Periods (Confirmatory Cohorts) 
Assessments 
Screening 
Perioda 
Evaluation Period 
Up to 36h 
 
 
-36h 
to up 
to -1h  
Base-
line 
Periodb 
up 
to -1h 
to 0h 
0h 
3h 
6h 
8h 
9h 
10h 
12h 
15h 
18h 
21h 
24h 
27h 
34h 
36h 
48h 
60h 
72h 
84h 
96hc 
(Assessment  
window) 
- 
- 
- 
(±15min) 
(±30min) 
Informed 
consentd 
X 
X 
-X- 
Subject 
identification 
card dispensing 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ex-
clusion criteria 
X 
Xe 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Table 5‒2: 
Schedule of study assessments – Screening and Evaluation Periods (Confirmatory Cohorts) 
Assessments 
Screening 
Perioda 
Evaluation Period 
Up to 36h 
 
 
-36h 
to up 
to -1h  
Base-
line 
Periodb 
up 
to -1h 
to 0h 
0h 
3h 
6h 
8h 
9h 
10h 
12h 
15h 
18h 
21h 
24h 
27h 
34h 
36h 
48h 
60h 
72h 
84h 
96hc 
(Assessment  
window) 
- 
- 
- 
(±15min) 
(±30min) 
Demographic 
data 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
including Apgar 
score and HIE 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs 
 
X 
X 
X 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
 
X 
 
X 
 
X 
Physical and 
neurological 
examination: 
Sarnat scale for 
subjects with 
HIE 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Length  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weightf 
X 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
Head 
circumference 
 
Xg 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary cause of 
seizure 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Psychometric 
parameters: 
N-PASS and 
EEG-parameters 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AED treatment 
(PB, MDZ, PHT, 
LEV 
Xn 
X 
 
 
(X) 
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Table 5‒2: 
Schedule of study assessments – Screening and Evaluation Periods (Confirmatory Cohorts) 
Assessments 
Screening 
Perioda 
Evaluation Period 
Up to 36h 
 
 
-36h 
to up 
to -1h  
Base-
line 
Periodb 
up 
to -1h 
to 0h 
0h 
3h 
6h 
8h 
9h 
10h 
12h 
15h 
18h 
21h 
24h 
27h 
34h 
36h 
48h 
60h 
72h 
84h 
96hc 
(Assessment  
window) 
- 
- 
- 
(±15min) 
(±30min) 
[≤60mg/kg/day], 
or LDC) 
Cohort 
Assignment 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BRV infusionh 
 
 
X 
 
 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
VEEGi 
-X- 
Heart rate 
monitoring 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
BRV PK 
samplesj 
 
 
Xj 
X 
 
X 
 
 
 
(X)j 
 
 
 
(X)j 
 
(X)k 
 
 
AED PK sample 
(only when PB 
and PHT are 
used) 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Laboratory 
assessments 
(safety)l 
 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
Thompson scorem 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Mechanical 
ventilation 
 
-X- 
AEs 
-X- 
Concomitant 
medications 
-X- 
Medical 
procedures 
-X- 
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Table 5‒2: 
Schedule of study assessments – Screening and Evaluation Periods (Confirmatory Cohorts) 
Assessments 
Screening 
Perioda 
Evaluation Period 
Up to 36h 
 
 
-36h 
to up 
to -1h  
Base-
line 
Periodb 
up 
to -1h 
to 0h 
0h 
3h 
6h 
8h 
9h 
10h 
12h 
15h 
18h 
21h 
24h 
27h 
34h 
36h 
48h 
60h 
72h 
84h 
96hc 
(Assessment  
window) 
- 
- 
- 
(±15min) 
(±30min) 
AEDsn 
-X- 
Infusion site 
reaction 
monitoringo 
 
 
X 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
X 
X 
X 
X 
X 
X 
Neurodevelop-
mental testing 
(Bayley-III 
score) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xp 
Dispense BRV 
dosing diary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Xq 
Dispense BRV 
for the BRV 
Extension Periodr 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
AE(s)=adverse events(s); AED(s)=antiepileptic drug(s); bid=twice daily; BRV=brivaracetam; BZD(s)=benzodiazepine(s); EEG=electroencephalography; 
ENS=electroencephalographic neonatal seizures; HIE=hypoxic-ischemic encephalopathy; ICF=Informed Consent form; iv=intravenous; LDC=lidocaine; 
LEV=levetiracetam; MDZ=midazolam; N-PASS=neonatal pain, agitation and sedation scale; PB=phenobarbital; PHT=phenytoin; PK=pharmacokinetic(s); 
VEEG=(multichannel) video-electroencephalography; (X)=optional for that day 
a Screening Period is from signing and dating of the written ICF up to initiation of the first BRV dose. 
b  The duration of the Baseline EEG depends on seizure activity. Subjects with intermittent seizures will enter the Evaluation Period based on at least 1 hour of 
EEG recording. Subjects in status epilepticus will enter the Evaluation Period based on up to 30 minutes of EEG recording, ie, as soon as 15 minutes of 
continuous seizures or 50% of cumulative seizure activity is confirmed on EEG.  
c If subjects do not benefit from BRV treatment after 96 hours of BRV administration, BRV administration will be stopped and replaced by another AED; 
however, the subject’s participation in the study will continue. Subjects discontinuing BRV treatment during the Evaluation Period should start the Down-
Titration Period while completing the Evaluation Period in parallel for the full 96 hours. 
d Parent(s) or legal representative(s) will be informed about the study as early as possible and asked to sign the informed consent after the occurrence of 
seizures is confirmed on VEEG. Continuous consent will be ensured by meetings between the Investigator (or designee) and the subject’s parent(s) or legal 
representative(s), during the conduct of the study. 
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Table 5‒2: 
Schedule of study assessments – Screening and Evaluation Periods (Confirmatory Cohorts) 
Assessments 
Screening 
Perioda 
Evaluation Period 
Up to 36h 
 
 
-36h 
to up 
to -1h  
Base-
line 
Periodb 
up 
to -1h 
to 0h 
0h 
3h 
6h 
8h 
9h 
10h 
12h 
15h 
18h 
21h 
24h 
27h 
34h 
36h 
48h 
60h 
72h 
84h 
96hc 
(Assessment  
window) 
- 
- 
- 
(±15min) 
(±30min) 
e The occurrence of ENS during the Baseline Period must be confirmed either by the local or central VEEG reader prior to drug administration. Preferably, the 
central VEEG reader should confirm the required ENS.  
f  Measurement of body weight is optional at 24, 48, 72, and 96 hours. Dosage of BRV during the Evaluation Period will be based on the subject’s weight 
measured prior to the start of the first BRV administration. However, dosage calculation can be adjusted to a more recent weight measurement, upon 
discretion of the Investigator, if weight is measured during the Evaluation Period. 
g Head circumference Baseline measurement should be taken within 7 days prior to drug administration, or at birth for subjects ≤7 days old. 
h Subjects will receive iv BRV 1mg/kg bid (2mg/kg/day), as recommended by the DMC on 05 Nov 2020 based on the results of the PK analysis of the 
Exploratory Cohort as well as an existing PK model from N01263.  
i  Video-EEGs that are acquired per standard of care prior to consenting and meet study-specific technical and quality requirements can be used as part of the 
Baseline assessment VEEG. 
j Following the first BRV infusion, 6 blood microsamples (60µL/sample) will be collected during the Evaluation Period from each subject. 
k The schedule of PK sampling for the Confirmatory Cohorts is also provided in Table 5‒5.  
l  For Screening and determination of eligibility, use of laboratory data acquired prior to Screening per standard of care inside or outside the study site within 
36 hours prior to the start of the Evaluation Period is allowed.    
m Thompson score will be used to measure the severity of HIE for subjects with HIE. 
n The recording of AEDs will include BZDs and opiates taken by the mother at the time of delivery. In addition, details regarding COVID-19 vaccination will 
be recorded as concomitant medication if mother was pregnant or breastfeeding when vaccinated.  
o Monitoring for BRV infusion site reactions should take place during and 30 minutes after the end of the infusion. The assessment will be conducted hourly 
from 0h to 3h of the BRV Evaluation Period. 
p The assessment of the Bayley-III score at 96-hour time point only applies to subjects who directly roll-over from the Evaluation Period to the long-term 
study due to their age at enrollment into N01349.  
q The BRV dosing diary will be dispensed only if the subject enters the BRV Extension Period. 
r Dispensing of BRV is only applicable if the subject enters the BRV Extension Period. 
 
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Table 5-3: 
Schedule of study assessments - BRV Extension Period and Safety 
Follow-Up Period (Exploratory and Confirmatory Cohorts) 
Assessments 
BRV Extension Period 
Down-
Titration 
Perioda 
Safety 
Follow-Up 
Periodb 
EPV1c 
EPV2d 
Unscheduled 
Visit 
Telephone 
Contact 
Up to 1 
week  
30 days 
(Assessment window) 
(±2 
days) 
- 
 
 
- 
(±3 days) 
Informed consente 
X 
X 
 
 
X 
 
Vital signs 
 
X 
X 
 
X 
X 
Physical and neurological 
examination: Sarnat scale for 
subjects with HIE 
 
X 
X 
 
Xf 
X 
Biometric parameters: length, 
body weight and head 
circumference 
 
 
 
 
 
X 
Primary cause of seizure 
 
 
 
 
Xf 
X 
Psychometric parameters: N-
PASS 
 
 
 
 
X 
X 
BRV administration or 
dispense 
X 
Xg 
 
 
Xh 
 
BRV return  
 
X 
 
 
 
 
1-hour VEEG 
 
 
 
 
Xi 
 
Laboratory assessments 
(safety) 
 
X 
Xo 
 
 
X 
Neurodevelopmental testing 
(Bayley-III score) 
 
Xj 
 
 
 
 
AE(s) 
-X- 
Concomitant medications 
-X- 
Medical procedures 
-X- 
AEDsk 
-X- 
Infusion site reaction 
monitoringl 
X 
X 
X 
 
X 
 
Confirmation/diagnosis of  
epilepsy 
 
X 
 
 
 
 
Update on Medical History 
 
Xm 
 
 
 
Xn 
Review BRV dosing diary 
X 
X 
X 
X 
 
 
AE(s)=adverse event(s); AED(s)=antiepileptic drug(s); BRV=brivaracetam; BZD(s)=benzodiazepine(s); 
EEG=electroencephalography; EPV=Extension Period Visit; HIE=hypoxic-ischemic encephalopathy; 
iv=intravenously; N-PASS=neonatal pain, agitation, and sedation scale; VEEG=(multichannel) 
video-electroencephalography 
Note: An Unscheduled Visit and a Telephone Contact are only applicable to subjects receiving oral BRV at home. 
a A Down-Titration Period of up to 1 week applies only to subjects in the Confirmatory Cohorts. The Down-Titration 
Period is recommended for subjects who discontinue BRV treatment prior to completion of the Evaluation Period, 
who do not proceed to the BRV Extension Period, or start the BRV Extension Period but do not enter the long-term 
study. Subjects discontinuing BRV treatment during the Evaluation Period can continue assessments pertaining to 
the Evaluation Period, except the collection of blood microsamples for the determination of BRV plasma 
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Table 5-3: 
Schedule of study assessments - BRV Extension Period and Safety 
Follow-Up Period (Exploratory and Confirmatory Cohorts) 
Assessments 
BRV Extension Period 
Down-
Titration 
Perioda 
Safety 
Follow-Up 
Periodb 
EPV1c 
EPV2d 
Unscheduled 
Visit 
Telephone 
Contact 
Up to 1 
week  
30 days 
(Assessment window) 
(±2 
days) 
- 
 
 
- 
(±3 days) 
concentrations. Those subjects should start the Down-Titration Period in parallel to completing the Evaluation 
Period.  
b Subjects will enter the Safety Follow-Up Period if they withdraw from the study at any time, or do not proceed to 
the BRV Extension Period, or complete the Down-Titration Period. This visit will occur 30±3 days after the last 
administration of BRV. For subjects unable to return to the hospital due to COVID-19, the Safety Follow-up Visit 
can be performed remotely. In this case vital signs, the physical and neurological examination, biometric and 
psychometric parameters, and the laboratory assessment may not be performed. 
c Subjects will attend EPV1 at 7±2 days after completion of the Evaluation Period. For subjects unable to return to 
the hospital due to COVID-19, EPV1 can be performed remotely if BRV oral solution was dispensed at the time 
when the subject completed the Evaluation Period.  
d Subjects will attend EPV2 when they enter the long-term study. Before entering the long-term study, subjects must 
have been switched to BRV oral solution and be able to tolerate it. Subjects who have not been switched to BRV 
oral solution will not be permitted to continue into the long-term study. The timing of switching from iv to oral 
solution will be at the discretion of the Investigator. Subjects will continue to receive the same BRV dose 
administered at the end of the Evaluation Period. 
e Parent(s) or legal representative(s) will be informed about the study as early as possible and asked to sign the 
informed consent after the occurrence of seizures is confirmed on VEEG. Continuous consent will be ensured by 
meetings between the Investigator (or designee) and the subject’s parent(s) or legal representative(s), during the 
conduct of the study. 
f To be performed on the first day of the Down-Titration Period only.  
g If the subject enters the long-term study, no study drug from N01349 will be dispensed in EPV2. If the subject does 
not enter the long-term study, BRV from N01349 will be administered for down-titration (only applicable to 
subjects from the Confirmatory Cohorts). 
h The Down-Titration steps and duration may be adjusted at the Investigator’s discretion.  
 i Video-EEG will only apply to subjects of the Confirmatory Cohorts who complete the study after the Evaluation 
Period. The VEEG will be recorded for at least 1 hour on the final day of the Down-Titration Period. Additional 
VEEGs can be performed at any time during the Down-Titration Period at the Investigator´s discretion. 
j Bayley-III assessment will be assessed for subjects continuing into the long-term study, in countries where a 
validated translation is available. 
k The recording of AEDs will include AEDs (BZDs and opiates) taken by the mother at the time of delivery. In 
addition, details regarding COVID-19 vaccination will be recorded as concomitant medication if mother was 
pregnant or breastfeeding when vaccinated. 
l Infusion site reactions will only be monitored for subjects receiving iv BRV. Monitoring for BRV infusion site 
reactions should take place during and 30 minutes after the end of the infusion. 
m Updated Medical History should be recorded at EPV2 for subjects entering the long-term study. 
n Updated Medical History should be recorded for subjects not entering the long-term study.  
o Laboratory assessment (safety) only required for Unscheduled Visits performed during the BRV Extension Period. 
 
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Table 5‒4: 
Schedule for PK Sampling (Exploratory Cohort)  
Assessment 
 
48-hour Evaluation Period 
Time relative to the start of the most recent BRV infusion  
Day 1 
Day 2a 
30-60minb 
2-4h 
8-12h 
30-60min 
2-4h 
8-12h 
BRV PK samplesc 
X 
X 
X 
X 
X 
X 
AED PK sample 
 
Xd 
 
 
 
 
AED=antiepileptic drug; BRV=brivaracetam; h=hours; min=minutes; PK=pharmacokinetic(s) 
Note: Blood for PK samples should be drawn from a line different to that of the BRV infusion. 
a Blood sampling is only needed on Day 2 if subjects are dosed with BRV on Day 2. 
b The first PK sample should be collected 30 to 60 minutes after the start of the BRV infusion.  
c The BRV PK sampling timepoints for the first 3 samples of the Exploratory Cohorts are as follows: 30 to 
60 minutes, 2 to 4 hours, and 8 to 12 hours after the start of the most recent BRV infusion. The second set of 
3 samples will be collected at the same timepoints on the second day of the 48-hour Evaluation Period. 
d The AED PK sample should be collected 3 hours after the start of the initial BRV administration. 
 
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Table 5‒5: 
Schedule for PK Sampling (Confirmatory Cohorts) 
Assessment 
96-hour Evaluation Period 
Time relative to the start of the most recent BRV infusion  
 
Day 1 
Day 2 
Day 3 
Day 4 
30-60mi
na 
2-4
h 
8-12
h 
30-60m
in 
2-4
h 
8-12
h 
30-60m
in 
2-4
h 
8-12
h 
30-60m
in 
2-4
h 
8-12
h 
BRV PK samp
lesb 
X 
X 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
AED PK 
sample 
 
Xc 
 
 
 
 
 
 
 
 
 
 
AED=antiepileptic drug; BRV=brivaracetam; h=hours; PK=pharmacokinetic(s); min=minutes; (X)=optional for 
that day 
Note: Blood for PK samples should be drawn from a line different to that of the BRV infusion.  
a The first PK sample will be collected 30 to 60 minutes after the start of the BRV infusion. 
b The BRV PK sampling timepoints for the first 3 samples of the Confirmatory Cohorts are as follows: 30 to 
60 minutes, 2 to 4 hours, and 8 to 12 hours after the start of the most recent BRV infusion. The second set of 
3 PK samples will be collected within the same timeframes as the first set on one of the following days: either 
Day 2 (post-24 hours), OR Day 3 (post-48 hours) OR Day 4 (post-72 hours). It is acceptable if these samples 
are drawn on different days. 
c The AED PK sample should be collected 3 hours after the start of the initial BRV administration. 
5.3 
Schematic diagrams 
Figure 5‒1 displays a schematic overview of the study for the Exploratory Cohort and the 
Screening and Evaluation Periods of this Cohort are presented in detail in Figure 5‒2. Figure 5‒3 
displays a schematic overview of the study for the Confirmatory Cohorts and the Screening and 
Evaluation Periods of these Cohorts are presented in detail in Figure 5‒4. 
 
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Figure 5‒1: Schematic overview of the study (Exploratory Cohort) 
 
 
AED=antiepileptic drug; BRV=brivaracetam  
a BRV to be administered in addition to another AED. 
 
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Figure 5‒2: Screening and Evaluation Periods (Exploratory Cohort) 
 
AED=antiepileptic drug; bid=twice daily; BRV=brivaracetam; EEG=electroencephalogram; ENS=electroencephalographic neonatal seizures; ICF=Informed 
Consent form; iv=intravenous; LEV=levetiracetam; LDC=lidocaine; MDZ=midazolam; PB=phenobarbital; PHT=phenytoin  
Note: The Screening Period is from signing and dating of the written ICF up to initiation of the first BRV dose. 
a BRV to be administered in addition to another AED. 
 
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Figure 5‒3: Schematic overview of the study (Confirmatory Cohorts) 
 
BRV=brivaracetam; PNA=postnatal age  
1 BRV Extension Period up to a PNA of 90 days is only applicable if subjects can intermittently not transition to a long-term study. 
 
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Figure 5‒4: Screening and Evaluation Periods (Confirmatory Cohorts) 
 
AED=antiepileptic drug; BRV=brivaracetam; EEG=electroencephalogram; ENS=electroencephalographic neonatal seizure; LEV=levetiracetam; 
LDC=lidocaine; MDZ=midazolam; PB=phenobarbital; PHT=phenytoin 
a  Concomitant treatment with AEDs is permitted to continue in parallel with BRV treatment if subjects are on a stable dose from 1 hour prior to initiation of 
BRV treatment. Changes to concomitant AEDs are permitted from 3 hours onward following first BRV administration). 
b Duration of the Baseline EEG depending on seizure activity: 
• 
for subjects with intermittent ENS: 1 hour 
• 
for subjects in status epilepticus: up to 30 minutes 
 
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5.4 
Rationale for study design and selection of dose 
5.4.1 
Rationale for study design 
The current accepted medical practice (ie, standard of care) for neonatal seizures is initial 
treatment with PB with rapid progression to treatment with MDZ for patients without adequate 
seizure control after 2 doses of PB. In more than 50% of subjects, seizures are not controlled 
after first-line treatment with PB or other AEDs, and subsequent treatment with additional AEDs 
does not significantly improve seizure control (van Rooij et al, 2013b; Castro Conde et al, 2005; 
Boylan et al, 2004; Painter et al, 1999). Thus, study N01349 was designed for a flexible 
treatment of ENS, and only those subjects who do not have adequate seizure control with 
previous AED treatment will be permitted to continue in the study. 
As the patient population of neonates with ENS is limited, the 2-step design of this study will 
allow confirmation (or adjustment) of dosing based on results from the first step (Exploratory 
Cohort) and evaluation of BRV efficacy in the second step (Confirmatory Cohorts). This 
adaptive design allows confirmation of dose and collection of PK, safety, and efficacy data, 
thereby potentially providing rapid access to alternative treatment in neonates. 
The frequency, voltage, and morphology of the discharges may change within an individual 
seizure and between seizures in an individual neonate. At enrollment, subjects must be at least 
34 weeks of CGA. In addition, term neonates up to 27 days of PNA and preterm neonates up to 
40 weeks of CGA and 27 days of PNA can be enrolled. Neonates undergoing hypothermia 
treatment (eg, for the treatment of HIE) will also be enrolled. 
Although newer AEDs are efficacious for the treatment of seizures in adults and older children, 
limited progress has been made in the treatment of neonatal seizures (Pressler et al, 2015; 
Pressler and Mangum 2013; Tulloch et al, 2012). Thus, clinical studies to assess the efficacy and 
safety of new treatment options in neonates are warranted. 
5.4.2 
Rationale for dose selection 
The doses planned to be applied in this study are based on pediatric data collected in N01263 
subjects (overall 96 subjects in the age range of 1 month to 17 years with the following number 
of subjects per pediatric age group: 1 month to <2 years of age, 29 subjects; 2 years to <6 years 
of age, 26 subjects; 6 years to <12 years of age, 24 subjects; 12 years to <16 years of age, 17 
subjects). A physiological-based PK model was used to extrapolate the PK of BRV from older 
children. It is estimated that a dose of BRV 0.5mg/kg bid, administered to neonatal subjects, 
should yield the same BRV exposure range in plasma as observed in older children receiving the 
same dose on a mg/kg body weight basis. In adults, a similar exposure is achieved with a dose of 
25mg bid, which represents the lowest dose approved for adults. A dose of 2mg/kg bid should 
result in similar exposure in neonates as compared to adults receiving 100mg bid (the highest 
approved dose in adults). Given the uncertainties of the extrapolation, as well as the variability 
and rapid changes in neonatal physiology, these predictions may or may not be precise; however, 
large discrepancies are not expected. 
Based on the extrapolation explained above, subjects who enter the Exploratory Cohort will 
receive an initial low dose of BRV (0.5mg/kg [bid]). A starting dose of BRV 0.5mg/kg was 
selected because this dose offers a wide safety margin (4-fold) with respect to the highest BRV 
dose administered and tolerated in older children and adults with epilepsy. Simultaneously, a 
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dose of BRV 0.5mg/kg is potentially therapeutically beneficial to subjects in this study. In 
adjunctive treatment studies, a dosage of BRV 25mg bid is effective for POS in adult subjects 
with epilepsy. 
For subjects who enter the Confirmatory Cohorts, the dosing frequency of BRV will be 
determined based on the PK findings of the Exploratory Cohort (see Section 5.1). The dose of 
BRV to be administered in the Confirmatory Cohorts will be determined by the evaluation of 
plasma samples collected in the Exploratory Cohort, as well as by the PK modeling of N01263 
data described above, and should not exceed the range of plasma concentrations observed in 
children ≥1 month old who received BRV 4mg/kg/day. The plasma concentration of BRV 
4mg/kg/day for neonates is predicted to be approximately equivalent to the plasma 
concentrations observed in adults who receive BRV 200mg/day. The dose in neonates to reach 
the same plasma concentrations will be confirmed or adapted upon completion of enrollment and 
analysis of PK and safety data from the Exploratory Cohort involving the DMC.  
The BRV dose used in the Confirmatory Cohorts will be based on recommendations made by the 
DMC. Based on the DMC meeting held on 05 Nov 2020, the BRV dose and frequency selected 
for the Confirmatory Cohorts is 1mg/kg bid (2mg/kg/day). Based on data from the Confirmatory 
Cohorts, the BRV dose may be further adjusted in a staggered approach as determined by the 
DMC. 
Furthermore, the posology of BRV for the Confirmatory Cohorts is proposed as an 
approximately 15-minute iv infusion in consideration of the following and is based on PK and 
safety data available from subjects ≥1 month old in N01263 and N01266: 
BRV is well-tolerated orally up to 200mg/day in adult subjects with epilepsy and in children 
1 month old to 16 years of age receiving up to 4mg/kg/day. In adults, a single iv infusion over 
15 minutes or a bolus of BRV up to 150mg/day is well-tolerated. A dose of BRV 4mg/kg/day is 
predicted to be approximately equivalent to the highest BRV dosage (200mg/day) received by 
adults. In addition, iv BRV is bioequivalent to the same dose given orally in healthy adults when 
given as a bolus or as a 15-minute infusion. 
Dose adjustment of BRV for the change in the formulation (switching from iv to oral solution) 
used during this study is not required as the AUC of BRV is bioequivalent between the following 
formulations: a tablet, a 15-minute iv infusion, and a bolus iv injection. In adults, iv BRV was 
administered to healthy volunteers, as well as subjects with epilepsy. Results showed that iv 
BRV was well-tolerated at all doses, up to 150mg per iv injection. Furthermore, the dose of BRV 
oral solution is bioequivalent to BRV tablets; therefore, dose adjustment is not required when 
switching between these formulations. 
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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 Independent Ethics Committee (IEC)-approved written ICF is signed and dated by the 
parent(s) or legal representative(s).  
2a. Confirmation on VEEG of ≥2 minutes of cumulative ENS or ≥3 identifiable ENS prior to 
entering the Evaluation Period (ENS is defined as a seizure lasting for at least 10 seconds on 
VEEG), despite receiving previous AED treatment for the treatment of 
electroencephalographic seizures.  
The occurrence of ENS during an up to 1-hour period must be confirmed either by the local 
or central VEEG reader prior to drug administration. Preferably, the central VEEG reader 
should confirm the required ENS. 
3. Subject is male or female and must be at least 34 weeks of CGA. In addition, term neonates up 
to 27 days of PNA and preterm neonates up to 40 weeks of CGA and 27 days of PNA can be 
enrolled.  
4. Subject weighs at least 2.3kg at the time of enrollment. 
5. Subjects with or without concomitant hypothermia treatment. 
6.2 
Exclusion criteria 
Subjects are not permitted to be enrolled in the study if any of the following criteria are met: 
1a. Subject receiving AED treatment other than PB, MDZ, PHT, LEV (≤60mg/kg/day), or LDC 
for the treatment of seizures prior to or at the time of enrollment (Confirmatory Cohorts 
only). 
2. Subject with seizures responding to any of the following: previous AED treatment 
immediately prior to BRV treatment, pyridoxine treatment, or correction of metabolic 
disturbances (hypoglycemia, hypomagnesemia, or hypocalcemia). 
3. Subject requires extra corporeal membrane oxygenation. 
4. Subject has seizures related to prenatal maternal drug use or drug withdrawal. 
5. Subject has known severe disturbance of hemostasis, as assessed by the Investigator. 
6. Subject has a poor prognosis for survival, as judged by the Investigator. 
7a. Subject has 2x upper limit of normal (ULN) of any of the following: aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), and alkaline phosphatase (ALP), 
with the following exception:  
 
For subjects with perinatal asphyxia, elevation of AST, ALT or ALP <5x ULN is acceptable, 
if initial and peak elevation of liver function tests (LFTs) occurs within 5 days after birth, and 
the time course of LFT elevation is compatible with hepatic injury due to perinatal asphyxia.  
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The determination of ULN will be based on the subject's gestational age (GA) and the site’s 
normal range values for the respective GA.8a. 
Subject has direct (conjugated) bilirubin 
levels >2mg/dL. 
9. Subject requiring or expected to require phototherapy or exchange transfusion due to 
elevated bilirubin. 
10. Subject with rapidly increasing bilirubin that may preclude the subject from inclusion in the 
study at the discretion of the Investigator. 
11 Subject with a severe cardiac condition, including subject with a diagnosis or signs of long 
QT syndrome (LQTS), and subject with a family history of LQTS. 
6.3 
Withdrawal criteria 
Parent(s) or legal representative(s) are free to withdraw the subject from the study at any time, 
without prejudice to continued care. 
Subjects must be withdrawn from the study if any of the following occur: 
1. The Sponsor or a regulatory agency requests withdrawal of the subject.  
2. Parent(s) or legal representative(s) withdraw their consent for the subject to participate. 
3. Subject is treated with prohibited concomitant medications as defined in this protocol. 
4a. Subject has direct (conjugated) bilirubin levels >2mg/dL. 
5. Subject requires phototherapy or exchange transfusion due to elevation of total bilirubin. 
6a. Subject has AST, ALT or ALP values 3x ULN, with the following exception: 
For subjects with perinatal asphyxia, elevation of AST, ALT or ALP <5x ULN is acceptable 
for continuation in the study, if initial and peak elevation of LFTs occurs within 5 days after 
birth, and if the time course of LFT elevation is compatible with hepatic injury due to 
perinatal asphyxia (ie, peak LFT elevation within a few days after birth, and subsequent 
normalization until up to day 14 after birth). 
In case AST, ALT or ALP elevation ≥5x ULN occurs within 5 days after birth, study drug 
must be discontinued and LFTs retested within 24 hours. If AST, ALT and ALP are 
confirmed to be <5x ULN, the subject may restart study drug after consultation with and 
approval by the Medical Monitor. 
The determination of ULN will be based on the subject's GA and the site’s normal range 
values for the respective GA. 
Subjects may be withdrawn from the study if any of the following events occur: 
7a. Subject experiences prolongation of seizure duration, a worsening of seizure burden, or 
emergence of new seizure type considered by the Investigator to require intervention.  
8. Investigator may withdraw subject due to any medical condition, based on clinical judgment 
and discretion. 
9a. Subject has AST, ALT or ALP values between >2x and ≤3x ULN, with the following 
exception:  
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For subjects with perinatal asphyxia, elevation of AST, ALT or ALP <5x ULN is acceptable 
for continuation in the study, if initial and peak LFT elevation occurs within 5 days after 
birth, and if the time course of LFT elevation is compatible with hepatic injury due to 
perinatal asphyxia (ie, peak LFT elevation within a few days after birth, and subsequent 
normalization until up to day 14 after birth). 
The determinations of ULN will be based on the subject’s GA and the site’s normal range 
values for the respective GA. 
10. Subject has rapidly increasing total bilirubin without requiring or being expected to require 
phototherapy or exchange transfusion; the subject’s withdrawal will be at the discretion of 
the Investigator. 
Investigators should attempt to obtain information on subjects in the case of withdrawal. The 
Investigator should document his/her effort (date and summary of the phone call and copy of the 
written message in the source documents) to complete the final evaluation. 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 eCRF must document the primary 
reason for withdrawal. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a subject in advance. 
6.3.1 
Potential drug-induced liver injury IMP discontinuation criteria 
Subjects with potential drug-induced liver injury (PDILI) must be assessed to determine if the 
investigational medicinal product (IMP) must be discontinued. In addition, all concomitant 
medications that are not medically necessary should also be discontinued.  
The PDILI criteria below require immediate and permanent discontinuation of IMP:  
• Subject has direct (conjugated) bilirubin >2mg/dL. 
• Subject has AST, ALT or ALP values >3x ULN, with the following exception: 
For subjects with perinatal asphyxia, elevation of AST, ALT or ALP <5x ULN is acceptable 
for continuation in the study, if initial and peak LFT elevation occurs within 5 days after 
birth, and if the time course of LFT elevation is compatible with hepatic injury due to 
perinatal asphyxia (ie, peak LFT elevation within few days after birth, and subsequent 
normalization until up to day 14 after birth).  
In case AST, ALT or ALP elevation ≥5x ULN occurs within 5 days after birth, study drug 
must be discontinued and LFTs retested within 24 hours. If AST, ALT and ALP are 
confirmed to be <5x ULN, the subject may restart study drug after consultation with and 
approval by the Medical Monitor. 
The determination of ULN will be based on the subject's GA and the site’s normal range 
values for the respective GA. 
• Subject requires or is expected to require phototherapy or exchange transfusion due to 
elevation of total bilirubin values. 
Investigators should attempt to obtain information on subjects in the case of IMP discontinuation 
to complete the final evaluation. Subjects with PDILI should not be withdrawn from the study 
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until investigation and monitoring are complete. All results of these evaluations and 
observations, as well as the reason(s) for IMP discontinuation and subject withdrawal (if 
applicable), must be recorded in the source documents. The eCRF must document the primary 
reason for IMP discontinuation. 
7 
STUDY TREATMENTS 
7.1 
Description of investigational medicinal products 
Only the following study drug will be supplied by UCB for N01349: 
• BRV 10mg/mL iv solution in a 5mL vial. 
For subjects who are switched to BRV oral solution in the BRV Extension Period, the following 
will be supplied by UCB: 
• BRV oral solution, at concentrations of 10mg/mL, will be supplied in 300mL glass bottles. 
Refer to the IMP Handling Manual for further details on the handling of BRV. 
There is no placebo or reference product. 
After the completion of the study, BRV treatment per SOC may be continued as prescribed but 
will not be provided by the Sponsor. 
7.2 
Treatments to be administered 
Subjects in the Exploratory Cohort will be dosed during the Evaluation Period with BRV 
(0.5mg/kg bid) according to the sites standard procedures. Treatment with AEDs per SOC 
(first-line, second-line, or subsequent treatment) will continue in parallel with BRV treatment. 
For subjects who enter the Confirmatory Cohorts, the dosing of BRV (1mg/kg bid [2mg/kg/day]) 
has been determined based on the PK findings of the Exploratory Cohort. The DMC will 
continue to monitor the PK and safety of the subjects and dosing may be adjusted as new data are 
available. Administration of BRV is proposed as approximately 15-minute iv infusions. 
Treatment with previous AEDs (PB, MDZ, PHT, LEV [≤60mg/kg/day], or LDC) during the 
Evaluation Period is permitted to continue if the subject is on a stable dose from 1 hour prior to 
initiation of the BRV treatment. 
Subjects can switch from iv to oral BRV at any time during the BRV Extension Period.  
For subjects who are switched to BRV oral solution, the dose will be measured using the 
appropriate syringes (1mL, 3mL or 10mL) with an adaptor able to fit all the bottle sizes. Oral 
solution should not be mixed with other liquids prior to administration. 
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7.3 
Packaging 
Brivaracetam (sterile solution for iv infusion and oral solution) is manufactured, packaged, and 
labeled according to Good Manufacturing Practice (GMP) guidelines and applicable laws or 
regulations. Brivaracetam is suitably packaged in such a way as to be protected from 
deterioration during transport and storage. 
Brivaracetam sterile solution for iv infusion 10mg/mL will be packaged in 5ml vials. 
Brivaracetam 10mg/mL oral solution will be packaged in 300mL type-III amber glass bottles 
with child-resistant tamper evident polypropylene screw closures. Syringes of 1mL, 3mL or 
10mL will be provided with an adaptor able to fit all the bottle sizes. 
Other AED treatments will be used for this study and will not be provided or covered by the 
Sponsor. 
7.4 
Labeling 
Clinical drug supplies will be labeled in accordance with the current International Council on 
Harmonisation (ICH) guidelines on Good Clinical Practice (GCP) and 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 pharmacist/designee) is responsible for the safe and proper storage of BRV 
at the site. Brivaracetam 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 completing a temperature log in accordance with local requirements on a 
regular basis (eg, once per working day), showing actual minimum/maximum temperatures 
reached over the time interval. 
Additional information pertaining to the handling of BRV, a Schedule V drug, is provided in the 
IMP Handling Manual. 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual. 
The Investigator (or designee) will instruct the subject to store the IMP following the instructions 
on the label. 
7.6 
Drug accountability 
A Drug Accountability form will be used to record BRV dispensing and return information on a 
by-subject basis and will serve as source documentation during the course of the study. Details of 
any BRV 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/ bottles of BRV until returned or destroyed. 
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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 BRV 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 containers/ bottles must be 
reconciled and either destroyed at the site according to local laws, regulations, and UCB 
Standard Operating Procedures (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 
After each iv BRV administration, empty/used BRV containers must be kept.  
All unused IMP and empty IMP containers/bottles must be accounted for or returned to the site. 
For subjects treated at home during the BRV Extension Period, parent(s) or legal 
representative(s) should be advised to return all unused IMP and empty IMP bottles to the site. 
Drug accountability must be done in the presence of the subject’s parent(s) or legal 
representative(s) and site staff to obtain explanations regarding discrepancies in compliance with 
the dosing regimen. Drug accountability must be recorded on the Drug Accountability form. 
Site personnel who are administering iv BRV will record information about all doses 
administered, including the target dose, actual dose administered, and the dates and times of 
initiation and completion of each iv administration. If the actual dose is less or more than the 
target dose, the reason a partial or excessive dose was administered will be recorded.  
Intravenous BRV solution will be administered under supervision of the Investigator or his/her 
designee. The noninjected volume will be recorded in the eCRF. Compliance with the 
recommended duration of the iv administration will also be assessed by recording the start time 
and the stop time in the eCRF.  
Noncompliance will be recorded for subjects who are administered <75% or >125% of the 
planned BRV dose. If, in the Investigator’s opinion, there is persistent noncompliance with the 
subject’s BRV administration, the Sponsor, in conjunction with the Investigator, will make a 
decision as to whether the subject should be withdrawn from the study. 
7.8 
Concomitant treatments and medications 
7.8.1 
Permitted concomitant treatments (medications and therapies) 
Concomitant treatment with non-AEDs is permitted for the Exploratory and Confirmatory 
Cohort(s) at any time throughout the study.  
For the Exploratory Cohort, concomitant treatment with AEDs is permitted at any time. 
For the Confirmatory Cohorts, concomitant treatment with AEDs is permitted to continue in 
parallel with BRV treatment if subjects are on a stable dose from 1 hour prior to initiation of 
BRV treatment. Changes to concomitant AEDs are permitted from 3 hours onward following 
first BRV administration. 
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7.8.2 
Prohibited concomitant treatments (medications and therapies) 
For the Confirmatory Cohorts, subjects will not be permitted to change concomitant treatment 
for neonatal seizures for the first 3 hours after the first BRV administration. 
The initiation of LEV treatment after the first time BRV is introduced is prohibited throughout 
the study for the Confirmatory Cohorts. 
7.8.3 
Rescue medication 
Any treatment initiation with a new AED, or any increase of dose or frequency of an existing 
concomitant AED for the treatment of seizures during the Evaluation Period is considered rescue 
treatment. Rescue medication can be given at any time if considered necessary by the 
Investigator. 
However, during the Evaluation Period rescue medication should not be administered – if 
possible – in the following time frames: 
• During the first 3 hours after the initial dose of BRV for the Confirmatory Cohorts. If this 
occurs, subjects will be considered BRV nonresponders for the evaluation of the main 
efficacy variable. 
7.9 
Blinding 
This is an open-label study and, therefore, no blinding is required. 
7.10 
Randomization and numbering of subjects 
Because N01349 is an open-label, single-arm study, subjects will not be randomized to any 
treatment groups. The first 6 subjects meeting the eligibility criteria will be assigned to the 
Exploratory Cohort. Subsequent subjects will be assigned to the Confirmatory Cohorts. 
An IRT system will be used to assign eligible subjects to a treatment regimen based on a 
predetermined packaging schedule provided by the Sponsor. The IRT will generate individual 
assignments for subject kits of BRV, as appropriate, according to the cohort assignment and 
dosing schedule. 
After the ICF has been signed and dated, the subject will be enrolled in the study. The 
Investigator or designee will contact the IRT and provide brief details about the subject enrolled. 
Each subject will be assigned a 5-digit number that serves as the subject identifier throughout the 
study. The IRT will allocate kit numbers to the subject based on the subject number during the 
course of the study. The subject number will be required in all communications between the 
Investigator or designee and the IRT on a particular subject. Subject numbers and kit numbers 
will be tracked via the IRT.  
8 
STUDY PROCEDURES BY VISIT  
A continuous consent process will be followed. Parent(s) or legal representative(s) will be 
informed about the study as early as possible and asked to sign the ICF after the occurrence of 
seizures has been confirmed by VEEG. During the course of the study, parent(s) or legal 
representative(s) will be updated about the care of their neonate, and continuous consent will be 
ensured by meetings between the Investigator (or designee) and the subject’s parent(s) or legal 
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representative(s). Continuous consent will be documented in the subjects’ medical charts and 
eCRF. 
8.1 
Exploratory Cohort 
8.1.1 
Screening Period 
The Screening Period will be from the signing and dating of the written ICF by the parent(s) or 
legal representative(s) up to initiation of the first BRV dose. Any AEs, AEDs, concomitant 
medications, and medical procedures will be collected after the ICF is signed. The subject’s 
eligibility to participate in this study will be assessed. The subject identification card will be 
dispensed. 
The Screening Period starts up to 36 hours prior to the first administration of BRV. 
Phenobarbital, MDZ, PHT, LEV, or LDC may have been administered prior to the subject’s 
enrollment into the study and/or at a location other than the study site. 
Subjects will enter the Evaluation Period and start BRV treatment as soon as the occurrence of 
ENS per inclusion criterion 2a is confirmed by the Investigator based on local EEG. If preferred 
by the Investigator, the central VEEG reader can be consulted to confirm the required ENS. 
The following assessments will be performed immediately before the first administration of BRV 
is initiated:  
• Verification of inclusion/exclusion criteria. Confirmation on VEEG of ≥2 minutes of 
cumulative ENS or ≥3 identifiable ENS prior to entering the Evaluation Period (ENS is 
defined as a seizure lasting for at least 10 seconds on VEEG), despite treatment with 1 or 
more AEDs administered per SOC  
• Vital signs (blood pressure, heart rate, respiratory rate [including apneas], oxygen saturation 
[pulse oximetry], and body temperature) 
• Physical and neurological examination (Sarnat scale for subjects with HIE; physical 
examination will include a check for the presence of skin rash and skin hypersensitivity) 
• Length  
• Body weight 
• Head circumference (to be taken within 7 days prior to drug administration, or at birth for 
subjects ≤7 days old)  
• Heart rate monitoring 
• Safety laboratory assessments (hematology, biochemistry, liver enzymes, and endocrinology) 
• Thompson score (for subjects with HIE) 
• Mechanical ventilation 
• AEs as reported by the Investigator 
• Recording of AEDs, concomitant medications, and medical procedures 
Laboratory measurements will be performed by local laboratories unless historical data is 
available. Historical safety laboratory assessments, previously collected as standard of care, may 
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be accepted from referring hospitals as measurement prior to first use of BRV if performed 
36 hours prior to the start of the Evaluation Period. In this case, test results will be considered 
medical history. Prior laboratory assessment results should be available and verified prior to 
initiation of the first BRV infusion. 
At the determination of the Investigator, subjects achieving adequate seizure control following 
AED treatment per SOC will be considered AED responders. Those subjects will be classified as 
screen failures and will not be assigned to BRV treatment. 
8.1.2 
Evaluation Period  
The first BRV infusion marks the starting point of the 48-hour Evaluation Period. 
An initial iv dose of BRV (0.5mg/kg) will be administered as an approximately 15-minute 
infusion. At the discretion of the Investigator, 3 additional iv BRV doses can be administered, up 
to a total of 4 iv BRV doses (0.5mg/kg bid) during the 48-hour BRV Evaluation Period.  
The following assessments will be performed after the end of the first BRV infusion:  
• Vital signs (blood pressure, heart rate, respiratory rate [including apneas], oxygen saturation 
[pulse oximetry], and body temperature; at 0, 3, 6, 12, 24, and 48 hours) 
• Physical and neurological examination (Sarnat scale for subjects with HIE; physical 
examination will include a check for the presence of skin rash and skin hypersensitivity; at 
24 hours and 48 hours) 
• Body weight (optional [at 24 and 48 hours]; dosage of BRV during the Evaluation Period 
will be based on the subject’s weight measured prior to the start of the first BRV 
administration. However, dosage calculation can be adjusted to a more recent weight 
measurement, upon discretion of the Investigator, if weight is measured during the 
Evaluation Period) 
• Confirmation of the primary cause of seizure (HIE, hemorrhage, or infarction; CNS 
malformations; CNS infections; undetermined causes [at 48 hours]) 
• N-PASS and EEG parameters for the assessment of sedation (at 48 hours) 
• Video-EEG  
• Heart rate monitoring (1, 2, 3, 6, 10, 12, 24, 27, 34, 36, and 48 hours) 
• Three to 6 PK samples (30 to 60 minutes, 2 to 4 hours, and 8 to 12 hours after the start of the 
most recent BRV infusion; the same timepoints apply to the first and second day of the 
48-hour Evaluation Period) 
• Collection of AED PK sample 3 hours after the start of the initial BRV administration 
• Safety laboratory assessments (hematology, biochemistry, liver enzymes, and endocrinology 
[at 48 hours]) 
• Thompson score (for subjects with HIE [at 48 hours]) 
• Mechanical ventilation 
• AEs as reported by the Investigator 
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• AEDs, concomitant medications, and medical procedures 
• Infusion site reaction monitoring  
8.1.3 
BRV Extension Period  
The BRV Extension Period is intended to bridge the time until subjects are old enough to 
participate in the long-term study. Subjects completing the Evaluation Period at a PNA of at least 
28 days may directly roll over to the long-term study, if they meet the eligibility criteria. Those 
patients are not required to enter the BRV Extension Period.  
At the end of the Evaluation Period, subjects who benefit from BRV treatment may enter the 
BRV Extension Period in accordance with the Investigator’s opinion. Subjects participating in 
the BRV Extension Period will need to remain at the study site as long as BRV is administered iv 
or via the enteral route. Only subjects able to swallow oral BRV should be allowed to be treated 
at home during the BRV Extension Period. In this case the parent(s) or legal representative(s) 
will receive a dosing diary to record the home administration of oral BRV. If oral BRV 
administration is not possible, the subjects will be invited to return to the study site and receive 
iv BRV as indicated below. It will not be possible for subjects to receive iv BRV at any 
institutions other than the study site.  
All subjects who participate in the BRV Extension Period must be offered entry into the 
long-term study, if they meet the eligibility criteria. Subjects will participate in the BRV 
Extension Period until they reach a stable condition that will allow them to enter the long-term 
study, if epilepsy is confirmed. The maximum anticipated duration of the BRV Extension Period 
per subject is up to 28 days of PNA (+7 days). For subjects entering the BRV Extension Period, 
study drug will be dispensed at the end of the Evaluation Period. Subjects not continuing the 
BRV treatment after they completed the Evaluation Period will not enter the BRV Extension 
Period but proceed immediately to the Safety Follow-Up Period (see Section 8.1.4). 
For subjects treated at home with oral BRV during the BRV Extension Period, a total of 2 on-site 
visits may take place (Extension Period Visit 1 [EPV1], Extension Period Visit 2 [EPV2]). 
Extension Period Visit 1 will be performed at 7±2 days after completion of the Evaluation Period 
(see Section 8.1.3.1). Extension Period Visit 2 will be performed on the same day when the 
subject enters the long-term study (see Section 8.1.3.2). If the long-term study is performed 
outside the N01349 hospital, an interval of up to 3 days between the N01349 EPV2 and 
follow-up study Entry Visit is allowed. In addition, an Unscheduled Visit or Telephone Contact 
can be performed, as needed. For subjects treated during the BRV Extension Period at the study 
site with iv BRV, assessments will be performed at timepoints described for EPV1 and EPV2.  
During the BRV Extension Period, subjects may continue receiving iv BRV but must switch to 
BRV oral solution before entering the long-term study. The timepoint of the switch from iv to 
oral solution will be at the discretion of the Investigator. Subjects who are not able to be dosed 
with BRV oral solution when they reach 28 days of postnatal age may continue in the BRV 
Extension Period for an additional 7 days; subjects who are not able to be switched to BRV oral 
solution by the end of the additional 7 days of the BRV Extension Period will not be eligible for 
enrollment in the long-term study.  
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Subjects who participate in the BRV Extension Period will continue to receive the same BRV 
dosage administered at the end of the Evaluation Period (ie, BRV 0.5mg/kg bid). The BRV dose 
should not be increased, but may be decreased at the discretion of the Investigator. 
8.1.3.1 
Extension Period Visit 1 
The EPV1 will be performed at 7±2 days after completion of the Evaluation Period. The 
following assessments will be performed: 
• BRV dispense 
• AEs as reported by the Investigator 
• AEDs, concomitant medications, and medical procedures 
• Review of BRV dosing diary (only if oral BRV is administered at home) 
• Infusion site reaction monitoring (for subjects treated with iv BRV) 
For subjects unable to return to the hospital due to COVID-19, EPV1 can be performed remotely 
if BRV oral solution was dispensed at the time when the subject completed the Evaluation 
Period. 
8.1.3.2 
Extension Period Visit 2 
The EPV2 should be performed on the same day when the subject enters the long-term study. 
The following assessments will be performed: 
• Vital signs (blood pressure, heart rate, respiratory rate [including apneas], oxygen saturation 
[pulse oximetry], and body temperature) 
• Physical and neurological examination (Sarnat scale for subjects with HIE; physical 
examination will include a check for the presence of skin rash and skin hypersensitivity) 
• BRV administration/dispense. If the subject enters the long-term study, no study drug from 
N01349 will be dispensed at EPV2. If the subject does not enter the long-term study, BRV 
from N01349 will be administered for down-titration (only applicable to subjects from the 
Confirmatory Cohorts).  
• BRV return  
• Safety laboratory assessments (hematology, biochemistry, liver enzymes, and endocrinology) 
• Bayley-III (for subjects continuing into the long-term study only and only for subjects 
enrolled in countries where a validated translation is available) 
• AEs as reported by the Investigator 
• AEDs, concomitant medications, and medical procedures 
• Review of BRV dosing diary (only if oral BRV is administered at home) 
• Infusion site reaction monitoring 
• Confirmation/diagnosis of epilepsy 
• Medical History (for subjects entering the long-term study) 
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8.1.3.3 
Unscheduled Visit 
An Unscheduled Visit can take place at any time during the BRV Extension Period. The 
following assessments will be performed: 
• Vital signs (blood pressure, heart rate, respiratory rate [including apneas], oxygen saturation 
[pulse oximetry], and body temperature) 
• Physical and neurological examination (Sarnat scale for subjects with HIE; physical 
examination will include a check for the presence of skin rash and skin hypersensitivity) 
• AEs as reported by the Investigator 
• AEDs, concomitant medications, and medical procedures 
• Review of BRV dosing diary Infusion site reaction monitoring 
8.1.3.4 
Telephone Contact 
For subjects receiving oral BRV at home, a Telephone Contact can be performed at any time 
during the BRV Extension Period. The following information will be collected by the 
Investigator: 
• AEs  
• AEDs, concomitant medications, and medical procedures 
• Discussion of BRV dosing diary 
8.1.4 
Safety Follow-Up Period 
Subjects will proceed to the Safety Follow-Up Period if they do not enter the BRV Extension 
Period. The visit will occur 30±3 days after the final administration of BRV. The following 
assessments will be performed: 
• Vital signs (blood pressure, heart rate, respiratory rate [including apneas], oxygen saturation 
[pulse oximetry], and body temperature) 
• Physical and neurological examination (Sarnat scale for subjects with HIE; physical 
examination will include a check for the presence of skin rash and skin hypersensitivity) 
• Body weight and length and head circumference  
• Primary cause of seizure (HIE, hemorrhage, or infarction; CNS malformations; CNS 
infections; undetermined causes) 
• N-PASS  
• Safety laboratory assessments (hematology, biochemistry, liver enzymes, and endocrinology) 
• AEs as reported by the Investigator 
• AEDs, concomitant medications, and medical procedures 
• Medical history (for subjects not entering the long-term study) 
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For subjects unable to return to the hospital due to COVID-19, the Safety Follow-Up Visit can 
be performed remotely. In this case vital signs, the physical and neurological examination, 
biometric and psychometric parameters, and the laboratory assessment may not be performed. 
8.2 
Confirmatory Cohorts 
Based on the PK and safety data review of the Exploratory Cohort by the DMC, enrollment and 
BRV dosing for the Confirmatory Cohorts will begin. Three consecutive Confirmatory Cohorts 
(n=12 each) are planned. A PK and safety data review will be performed after completion of 
each of the 3 Confirmatory Cohorts. During the PK and safety data review, the recruitment of 
subjects will continue. 
8.2.1 
Screening Period 
The Screening Period will be from the signing and dating of the written ICF by the parent(s) or 
legal representative(s) of the subject up to initiation of the first BRV dose. Any AEs, AEDs, 
concomitant medications, and medical procedures will be collected after the ICF is signed. The 
subject’s eligibility to participate in this study will be assessed. The subject identification card 
will be dispensed. 
The Screening Period starts up to 36 hours prior to the first administration of BRV. The 
treatment with one or more of the following AEDs prior to or at the time of enrollment: PB, 
MDZ, PHT, LEV (≤60mg/kg/day), or LDC (first-line, second-line, or subsequent treatment; 
choice of treatment, dose, and dosing regimen at the Investigator’s discretion) may have started 
prior to the subject’s enrollment in the study and/or at a location other than the study site.  
At the determination of the Investigator, subjects achieving adequate seizure control following 
any of the following AEDs: PB, MDZ, PHT, LEV (≤60mg/kg/day), or LDC will be considered 
AED responders. Those subjects will be classified as screen failures and will not be assigned to 
BRV treatment. 
8.2.1.1 
Baseline Period 
The Baseline Period will be up to 1 hour immediately prior to the start of initial BRV infusion 
and depend on seizure activity:  
• For subjects with intermittent ENS: at least 1 hour prior to entering the Evaluation Period 
• For subjects in status epilepticus: up to 30 minutes prior to entering the Evaluation Period. At 
least 15 minutes of continuous seizures, or 50% of cumulative seizure activity during a 
30-minute interval are to be confirmed on EEG before the administration of BRV can start. 
As soon as subjects are considered to be in status epilepticus, steps required for the preparation 
of the initial BRV infusion can be initiated (eg, assignment of BRV kits through interactive IRT 
and the dilution of BRV solution for iv infusion), even if the required EEG recording is not 
completed by that time.  
The occurrence of ENS during the Baseline Period must be confirmed either by the local or 
central VEEG reader prior to drug administration. Preferably, the central VEEG reader should 
confirm the required ENS. Video-EEGs that are acquired per standard of care prior to consenting 
and meet study-specific technical and quality requirements (eg, ability for immediate cloud-
based central review) can be used as part of the Baseline assessment VEEG.  
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The following assessments will be performed during the Baseline Period: 
• Verification of inclusion/exclusion criteria. Confirmation on VEEG of ≥2 minutes of 
cumulative ENS or ≥3 identifiable ENS within the up to 1 hour prior to entering the 
Evaluation Period (ENS is defined as a seizure lasting for at least 10 seconds on VEEG), 
despite treatment with one or more AEDs per SOC 
• Demographic data 
• Medical history (including Apgar score) 
• Vital signs (blood pressure, heart rate, respiratory rate [including apneas], oxygen saturation 
[pulse oximetry], and body temperature) 
• Physical and neurological examination (Sarnat scale for subjects with HIE; physical 
examination will include a check for the presence of skin rash and skin hypersensitivity) 
• Length  
• Body weight 
• Head circumference (Baseline measurement should be taken within 7 days prior to drug 
administration, or at birth for subjects ≤7 days old)  
• Primary cause of seizure (HIE, hemorrhage, or infarction; CNS malformations; CNS 
infections; undetermined causes) 
• N-PASS and EEG parameters for the assessment of sedation 
• Video-EEG 
• Heart rate monitoring 
• Safety laboratory assessments (hematology, biochemistry, liver enzymes, and endocrinology) 
• Thompson score (for subjects with HIE) 
• Mechanical ventilation 
• AEs as reported by the Investigator 
• AEDs, concomitant medications, and medical procedures 
Baseline laboratory measurements will be performed by local laboratories unless historical data 
is available. Historical safety laboratory assessments, previously collected as standard of care, 
may be accepted from referring hospitals as Baseline measurement if performed 36 hours prior to 
the start of the Evaluation Period. In this case, test results will be considered medical history. 
Prior laboratory assessment results should already be available at Baseline and verified prior to 
initiation of BRV administration.   
8.2.2 
Evaluation Period 
The first administration of BRV marks the starting point of the Evaluation Period.  
Up to 8 iv doses of BRV (1mg/kg bid) will be administered as an approximately 15-minute 
infusion during the 96-hour BRV Evaluation Period. The AED treatment initiated prior to first 
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administration of BRV can be continued if the subject is on a stable dose for at least 1 hour at the 
time the first BRV infusion is initiated. 
If subjects do not benefit from BRV treatment after 96 hours of BRV administration, BRV 
administration will be stopped and replaced by another AED; however, the subjects´ 
participation in the study will continue. 
If subjects in the Confirmatory Cohort receive <8 BRV doses, those subjects are allowed to 
continue study participation and complete study assessments per Table 5‒2 with the exception of 
PK blood sampling. Those subjects should start the Down-Titration Period while completing the 
Evaluation Period in parallel for the full 96 hours. 
After the enrollment of subjects, the weight of the subject will be measured and BRV will be 
given.  
The following assessments will be performed after BRV administration: 
• Vital signs (blood pressure, heart rate, respiratory rate [including apneas], oxygen saturation 
[pulse oximetry], and body temperature; at 0, 3, 6, 9, 12, 15, 18, 21, 24, 48, 72, and 96 hours) 
• Physical and neurological examination (Sarnat scale for subjects with HIE; physical 
examination will include a check for the presence of skin rash and skin hypersensitivity [at 
24, 48, 72, and 96 hours]) 
• Primary cause of seizure (HIE, hemorrhage, or infarction; CNS malformations; CNS 
infections; undetermined causes [at 96 hours]) 
• N-PASS and EEG parameters for the assessment of sedation (at 96 hours) 
• Body weight (optional [at 24, 48, 72 and 96 hours]; dosage of BRV during the Evaluation 
Period will be based on the subject’s weight measured prior to the start of the first BRV 
administration. However, dosage calculation can be adjusted to a more recent weight 
measurement, upon discretion of the Investigator, if weight is measured during the 
Evaluation Period) 
• Video-EEG 
• Heart rate monitoring  
• Up to 6 PK samples (30 to 60 minutes, 2 to 4 hours, and 8 to 12 hours after the start of the 
most recent BRV infusion; the same timepoints apply to the first day and 1 of the 3 following 
days of the 96-hour Evaluation Period). 
• Collection of AED PK sample 3 hours after the start of the initial BRV administration 
• Safety laboratory assessments (hematology, biochemistry, liver enzymes, and endocrinology 
[at 24 and 96 hours]) 
• Thompson score (for subjects with HIE [at 96 hours]) 
• Mechanical ventilation 
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• Bayley-III (for subjects continuing into the long-term study only and only for subjects 
enrolled in countries where a validated translation is available)  
• AEs as reported by the Investigator  
• AEDs, concomitant medications, and medical procedures 
• Infusion site reaction monitoring  
8.2.3 
BRV Extension Period  
The BRV Extension Period is intended to bridge the period until subjects are old enough to 
participate in the long-term study. Subjects completing the Evaluation Period at a PNA of at least 
28 days may directly roll over to the long-term study, if they meet the eligibility criteria. Those 
patients are not required to enter the BRV Extension Period. 
At the end of the Evaluation Period, subjects who benefit from BRV treatment may enter the 
BRV Extension Period in accordance with the Investigator’s opinion. Subjects participating in 
the BRV Extension Period will need to remain at the study site as long as BRV is administered 
iv. Only subjects able to swallow oral BRV should be allowed to be treated at home during the 
BRV Extension Period. If oral BRV administration is not possible, the subjects will be invited to 
return to the study site and receive iv BRV as indicated below. It will not be possible for subjects 
to receive iv BRV at any institutions other than the study site. All subjects who participate in the 
BRV Extension Period must be offered entry into the long-term study, if they meet the eligibility 
criteria. Subjects will participate in the BRV Extension Period until they reach a stable condition 
that will allow them to enter the long-term study, if epilepsy is confirmed. The maximum 
anticipated duration of the BRV Extension Period per subject is up to 90 days of PNA. For 
subjects entering the BRV Extension Period, study drug will be dispensed at the end of the 
Evaluation Period. Subjects not continuing the BRV treatment after they completed the 
Evaluation Period will not enter the BRV Extension Period but proceed immediately to the 
Down-Titration Period (see Section 8.2.4). 
For subjects treated at home with oral BRV during the BRV Extension Period, a total of 2 on-site 
visits may take place (EPV1 and EPV2). Extension Period Visit 1 will be performed at 7±2 days 
after completion of the Evaluation Period (see Section 8.2.3.1). Extension Period Visit 2 will be 
performed on the same day when the subject enters the long-term study (see Section 8.2.3.2). If 
the long-term study is performed outside the N01349 hospital, an interval of up to 3 days 
between the N01349 EPV2 and long-term study Entry Visit is allowed. In addition, an 
Unscheduled Visit or Telephone Contact can be performed, as needed. For subjects treated 
during the BRV Extension Period at the study site with iv BRV, assessments will be performed 
at timepoints described for EPV1 and EPV2. 
During the BRV Extension Period, subjects may continue receiving iv BRV but must switch to 
BRV oral solution before entering the long-term study. The timepoint of the switch from iv to 
oral solution will be at the discretion of the Investigator 
Subjects who participate in the BRV Extension Period will continue to receive the same BRV 
dosage administered at the end of the Evaluation Period (ie, BRV 1mg/kg bid). The BRV dose 
should not be increased, but may be decreased at the discretion of the Investigator. 
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In the event that a long-term study is temporarily not available after the planned duration of the 
BRV Extension Period (28 [+7] days of PNA), subjects are allowed to remain in the BRV 
Extension Period until they reach a PNA of up to 90 days. For those subjects, the assessments 
planned for Unscheduled Visits (Section 8.2.3.3) will be conducted in intervals of approximately 
30 days during the prolonged Extension Period.  
8.2.3.1 
Extension Period Visit 1 
This visit will be performed at 7±2 days after completion of the Evaluation Period. The 
following assessments will be performed: 
• BRV dispense 
• AEs as reported by the Investigator 
• AEDs, concomitant medications, and medical procedures 
• Review of BRV dosing diary (only if oral BRV is administered at home) 
• Infusion site reaction monitoring (for subjects treated with iv BRV) 
For subjects unable to return to the hospital due to COVID-19, EPV1 can be performed remotely 
if BRV oral solution was dispensed at the time when the subject completed the Evaluation 
Period. 
8.2.3.2 
Extension Period Visit 2 
This visit should be performed on the same day when the subject enters the long-term study. The 
following assessments will be performed:  
• Vital signs (blood pressure, heart rate, respiratory rate [including apneas], oxygen saturation 
[pulse oximetry], and body temperature) 
• Physical and neurological examination (Sarnat scale for subjects with HIE; physical 
examination will include a check for the presence of skin rash and skin hypersensitivity)  
• BRV administration/dispense. If the subject enters the long-term study, no study drug from 
N01349 will be dispensed at EPV2. If the subject does not enter the long-term study, BRV 
from N01349 will be administered for down-titration (only applicable to subjects from the 
Confirmatory Cohorts).  
• BRV return  
• Safety laboratory assessments (hematology, biochemistry, liver enzymes, and endocrinology) 
• Bayley-III (for subjects continuing into the long-term study only and only for subjects 
enrolled in countries where a validated translation is available) 
• AEs as reported by the Investigator 
• AEDs, concomitant medications, and medical procedures 
• Review of BRV dosing diary (only if oral BRV is administered at home) 
• Infusion site reaction monitoring (for subjects treated with iv BRV) 
• Confirmation/diagnosis of epilepsy  
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• Medical History (for subjects entering the long-term study) 
8.2.3.3 
Unscheduled Visit 
An Unscheduled Visit can take place at any time during the BRV Extension Period. The 
following assessments will be performed: 
• Vital signs (blood pressure, heart rate, respiratory rate [including apneas], oxygen saturation 
[pulse oximetry], and body temperature) 
• Physical and neurological examination (Sarnat scale for subjects with HIE; physical 
examination will include a check for the presence of skin rash and skin hypersensitivity) 
• Safety laboratory assessments (hematology, biochemistry, liver enzymes, and endocrinology) 
• AEs as reported by the Investigator 
• AEDs, concomitant medications, and medical procedures 
• Review of BRV dosing diary 
• Infusion site reaction monitoring 
For subjects who remain in the BRV Extension Period for a prolonged duration (ie, until they 
reach a PNA of 90 days), these assessments will be conducted at intervals of 30 (±3 days).  
8.2.3.4 
Telephone Contact 
For subjects receiving oral BRV at home, a Telephone Contact can be performed at any time 
during the BRV Extension Period. The following information will be collected by the 
Investigator: 
• AEs  
• AEDs, concomitant medications, and medical procedures 
8.2.4 
Down-Titration Period 
A Down-Titration Period of up to 1 week is recommended for subjects who complete the 
Evaluation Period, but do not enter the BRV Extension Period, discontinue BRV during the 
Evaluation Period, or start the BRV Extension Period but do not continue into the long-term 
study for any reason. The Down-Titration steps and duration may be adjusted at the 
Investigator’s discretion.  
The following assessments will be performed: 
• Vital signs (blood pressure, heart rate, respiratory rate [including apneas], oxygen saturation 
[pulse oximetry], and body temperature) 
• Physical and neurological examination (Sarnat scale for subjects with HIE; physical 
examination will include a check for the presence of skin rash and skin hypersensitivity; to 
be performed on the first day of the Down-Titration Period only) 
• Primary cause of seizure (HIE, hemorrhage, or infarction; CNS malformations; CNS 
infections; undetermined causes; to be performed on the first day of the Down-Titration 
Period only) 
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• N-PASS  
• BRV administration 
• At least a 1-hour video-EEG on the final day of the Down-Titration Period (during the 
Down-Titration Period, additional VEEGs can be performed at the Investigator´s discretion)  
• AEs as reported by the Investigator 
• AEDs, concomitant medications, and medical procedures 
• Infusion site reaction monitoring 
8.2.5 
Safety Follow-Up Period 
Subjects will proceed to the Safety Follow-Up Period once they complete the Down-Titration 
Period. This visit will occur 30±3 days after the final administration of BRV. The following 
assessments will be performed: 
• Vital signs (blood pressure, heart rate, respiratory rate [including apneas], oxygen saturation 
[pulse oximetry], and body temperature) 
• Physical and neurological examination (Sarnat scale for subjects with HIE; physical 
examination will include a check for the presence of skin rash and skin hypersensitivity) 
• Body weight and length and head circumference 
• Confirmation of the primary cause of seizure (HIE, hemorrhage, or infarction; CNS 
malformations; CNS infections; undetermined causes) 
• N-PASS  
• Safety laboratory assessments (hematology, biochemistry, liver enzymes, and endocrinology) 
• AEs as reported by the Investigator 
• AEDs, concomitant medications, and medical procedures 
• Medical History (for subjects not entering the long-term study) 
For subjects unable to return to the hospital due to COVID-19, the Safety Follow-Up Visit can 
be performed remotely. In this case vital signs, the physical and neurological examination, 
biometric and psychometric parameters, and the laboratory assessment may not be performed. 
9 
ASSESSMENT OF PHARMACOKINETIC VARIABLES 
9.1 
Pharmacokinetic sampling and handling 
For the determination of plasma concentrations of BRV and BRV metabolites, up to 6 blood 
microsamples (60μL/sample) will be collected per subject in the Exploratory (3 to 6 blood 
microsamples) and Confirmatory Cohorts (up to 6 blood microsamples) at 3 predetermined 
timepoints per day. An additional microsample (60μL) will be collected per subject for the 
determination of plasma concentrations of concomitant AEDs (PB and PHT).  
Pharmacokinetic samples will be obtained either through a venous or arterial catheter or taken 
from routinely performed heel-pricks. Blood for PK samples should be drawn from a line 
different to that of the BRV infusion. Three BRV PK samples of blood will be collected at the 
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following predetermined timepoints at the first day of the Evaluation Period: 30 to 60 minutes, 
2 to 4 hours, and 8 to 12 hours after the start of the most recent BRV infusion. For the 
Exploratory Cohort the same timepoints apply to the second day of the 48-hour Evaluation 
Period. For the Confirmatory Cohort(s), the second set of 3 BRV PK samples will be collected at 
the same timepoints on 1 of the other days of the 96-hour Evaluation Period. It will be acceptable 
if these samples are drawn on different days. The AED PK sample should be collected 3 hours 
after the start of the initial BRV administration. The timepoints for the collection of PK samples 
are described in Table 5‒4 for the Exploratory Cohort and in Table 5‒5 for the Confirmatory 
Cohorts.  
Additional opportunistic blood samples for the PK analysis (Leroux et al, 2015) may be obtained 
at the Investigator’s discretion at any time during the Evaluation Period. As opportunistic blood 
samples will be taken from routine laboratory blood samples, they are not considered an 
additional burden for the neonates. The plan for microsampling in N01349 is consistent with 
blood sampling schema in other neonatal studies (Allegaert and van den Anker, 2015; Jullien et 
al, 2015; O’Hara et al, 2015; Zhao and Jacqz-Aigrain, 2015; Zhao et al, 2014). 
Exact dosing and sampling times will be recorded in the eCRF. Sampling times of 
pre-determined PK samples may be subject to change after analysis and review of data from the 
Exploratory Cohort to complete the PK profile.  
The full set of a subject’s PK plasma samples will be shipped for analyses after the subject has 
completed the Evaluation Period. 
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9.2 
Pharmacokinetic sample shipment 
Instructions on blood sample collection, processing, storage, and labeling/shipping will be 
provided in the laboratory manual for this study. On arrival, the samples will be stored at -20°C, 
until analysis. 
Shipments due to arrive over the weekend or holidays must be avoided. For PK samples 
collected over a weekend in the site, these should be stored at -20°C and must be shipped under 
frozen conditions (packaged with dry ice) to the central laboratory on the following Monday. 
Prior to any shipment, an agreement must be made with the analytical laboratory for receipt of 
the samples. 
10 
ASSESSMENT OF EFFICACY 
10.1 
Assessment of the secondary efficacy variables (Confirmatory 
Cohort[s] only) 
The main secondary efficacy variable is: 
• Proportion of responders to BRV treatment from Baseline to 3 hours after the initial BRV 
dose 
A BRV responder is defined as a subject who achieved the following reduction in seizure 
burden (ENS in minutes per hour) without need for rescue medication, compared to the 
seizure burden measured during the Baseline Period immediately prior to BRV 
administration, evaluated for a 2-hour period starting 1 hour after the start of initial BRV 
treatment: 
− At least 80% reduction in nonsevere seizure burden  
(Nonsevere seizure burden is defined as ≤50% seizure activity on VEEG in all 30-minute 
timespans) 
OR 
− At least 50% reduction in severe seizure burden 
A severe seizure burden is defined as >50% seizure activity on VEEG in any 30-minute 
timespan. Timespans of 30 minutes refer to the following intervals within the 2-hour 
period: 0 to ≤30 minutes, >30 to ≤60 minutes, >60 to ≤90 minutes, and >90 to ≤120 
minutes 
For this study, an ENS is defined as EEG seizure lasting for at least 10 seconds on VEEG.  
Baseline seizure burden is defined as seizure burden measured on the continuous VEEG (total 
ENS in minutes per hour) during a period of up to 1 hour immediately prior to the first 
administration of study drug. 
For the analysis of the main secondary efficacy variable (Section 4.2.1), subjects who started 
another AED, increased the dose or frequency of administration of an AED ongoing at the time 
the first BRV infusion started, or are switched to another AED, or have been administered any 
rescue medication for the treatment of ENS during the first 3 hours after initiation of BRV 
treatment will be considered BRV nonresponders.  
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For the analysis of the following secondary efficacy variables, subjects who started another 
AED, increased the dose or frequency of administration of an AED ongoing at the time the first 
BRV infusion started, or are switched to another AED, or have been administered any rescue 
medication for the treatment of ENS following the first 3 hours after initiation of BRV treatment 
will be considered BRV responders: 
• Proportion of subjects with at least 80% reduction in nonsevere seizure burden from Baseline 
to 3 hours after the initial BRV treatment 
• Proportion of subjects with at least 50% reduction in severe seizure burden from Baseline to 
3 hours after the initial BRV treatment 
• Absolute reduction in average seizure burden measured by continuous VEEG from Baseline 
to the end of the 96-hour Evaluation Period 
• Percent reduction in average seizure burden measured by continuous VEEG from Baseline to 
the end of the 96-hour Evaluation Period 
• Proportion of BRV responders at the end of the 96-hour Evaluation Period  
• Proportion of subjects who are seizure-free (100% reduction in seizure burden from 
Baseline) at 24 hours following the start of initial BRV treatment, categorized by subjects 
with nonsevere or severe seizure burden at Baseline 
• Time to reduction in seizure burden for BRV responders (defined as the first timepoint when 
BRV responder criteria were met) 
• Seizure freedom at the end of the Down-Titration Period  
• Rate of at least 50% reduction in ENS frequency per hour from Baseline to the end of the 
96-hour Evaluation Period 
• Proportion of subjects who are seizure-free by time interval at 3 hours, at 3-hour intervals 
thereafter through 24 hours, and every 12 hours to 24 hours following the start of the initial 
BRV treatment 
• Absolute difference in clinical seizures at the end of the 24-hour Evaluation Period from 
Baseline for neonates with motor seizures at the time of inclusion 
• Percent difference in clinical seizures at the end of the 24-hour Evaluation Period from 
Baseline for neonates with motor seizures at the time of inclusion 
10.2 
Assessment of other efficacy variables 
Other efficacy variables will include: 
• Absolute and percentage reduction from Baseline in seizure burden at evaluation periods of 
0 hours to 3 hours, >3 hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, 
>24 hours to 36 hours, >36 hours to 48 hours, >48 hours to 72 hours, and >72 hours to 
96 hours after the start of initial BRV treatment 
• Categorized percentage reduction from Baseline to the end of the 96-hour Evaluation Period 
in seizure burden (<-25% [worsening], -25% to <25% [no change], 25% to <50%, 50% to 
<80%, and ≥80%)  
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• Proportion of BRV responders by time interval at evaluation periods of 0 to 3 hours, >3 to 
6 hours, >6 to 12 hours, >12 to 24 hours, >24 to 36 hours, >36 to 48 hours, >48 to 72 hours, 
and >72 to 96 hours after the start of initial BRV treatment 
• Proportion of subjects who switch over from BRV to another AED during the 96-hour 
Evaluation Period 
• Proportion of responders to other treatment during the 96-hour Evaluation Period (including 
at the end of the 96-hour Evaluation Period, and by time intervals: 0 hours to 3 hours, 
>3 hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, >24 hours to 36 hours, 
>36 hours to 48 hours, >48 hours to 72 hours, and >72 hours to 96 hours after the start of 
initial BRV treatment) 
(A responder to other treatment is defined as at least 80% reduction in nonsevere seizure 
burden from start of other treatment to end of other treatment or at least 50% reduction in 
severe seizure burden from the initiation of other treatment to end of other treatment during 
the 96-hour Evaluation Period). 
To further evaluate BRV efficacy, a descriptive comparison will be conducted of the main 
efficacy variable data from N01349 with published responder rates for one or more AED 
treatments from literature (historical control group matched in age and condition) effective for 
the treatment of neonatal seizures in subjects of similar age (<29 days of PNA) and condition 
(neonatal seizures as noted in N01349 eligibility criteria). A recent study (Weeke et al, 2016) 
provides response rates for second line AED treatment of neonatal seizures in a similar 
population and with primary endpoints comparable to N01349. Results from this study, as well 
as results from other studies available in the literature at the time of N01349 completion and with 
populations and efficacy endpoints comparable to N01349, will be used for these comparisons. 
10.3 
Seizure burden 
Seizure burden is defined as the total minutes of ENS per hour. Seizure burden information will 
be recorded for the Confirmatory Cohorts via a continuous VEEG. Seizure burden at Baseline 
will be evaluated over a period of at least 1 hour (subjects with intermittent seizures) or up to 
30 minutes (subjects in status epilepticus). 
Electroencephalographic neonatal seizures are defined as EEG seizures occurring for at least 
10 seconds. 
Seizure counts/seizure burden will be based on data collected using continuous VEEG. The 
VEEG recording will be evaluated by the local physician or central reader to evaluate eligibility 
of the subject. The VEEG recordings will subsequently be confirmed and quantified by the 
central reader at the end of the study. 
11 
ASSESSMENT OF SAFETY 
11.1 
Adverse events 
11.1.1 
Definitions 
11.1.1.1 
Adverse event 
An 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 
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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 ICF), including any pretreatment and posttreatment periods required by the 
protocol, must be recorded even if no IMP was taken but specific study procedures were 
conducted. This includes all AEs not present prior to the signing of the ICF and all AEs that 
recurred or worsened after the signing of the ICF. 
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 based on assessments performed prior to the first 
administration of BRV. 
11.1.1.2 
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, 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 
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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). 
11.1.1.2.1 
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:  
• Respiratory distress syndrome 
• Convulsion 
This original list will remain in effect for the duration of the protocol. 
In addition, the following are anticipated SAEs in babies with HIE: 
Acute 
• Anuria/kidney failure 
• Clotting aberrations up to disseminated intravascular coagulation  
• Hypotonia 
• Blood pressure instability 
• Cardio-respiratory failure 
• Multiorgan failure 
• Severe encephalopathy with coma 
• Status epilepticus 
• Cerebral oedema 
• Death 
Chronic 
• Cerebral palsy 
• Visual Impairment 
• Epilepsy 
• Learning Difficulties 
• Behavioural Difficulties 
These lists do not change the Investigator’s obligation to report all SAEs (including anticipated 
SAEs) as detailed in Section 11.1.2.3. 
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11.1.1.3 
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. 
The following will be considered AEs of special interest for the study population: 
• Autoimmune nephritis 
• Nephritis 
• Nephritis allergic 
• Tubulointerstitial nephritis 
• Tubulointerstitial nephritis and uveitis syndrome 
• Potential drug-induced liver injury as indicated by: 
− Direct (conjugated) bilirubin >2mg/dL 
− Condition requiring phototherapy or exchange transfusion due to elevation total of 
bilirubin values 
− AST, ALT or ALP values ≥3x ULN according to the subject’s GA and the site’s normal 
values for that GA, with the following exception: 
For subjects with perinatal asphyxia, if initial and peak LFT elevation occurs 
within 5 days after birth, and if the time course of the elevation of LFT is compatible with 
hepatic injury due to perinatal asphyxia (ie, peak LFT elevation within few days after 
birth, and subsequent normalization until up to day 14 after birth) only AST, ALT or 
ALP elevation ≥5x ULN must be reported as an AE of special interest. 
11.1.2 
Procedures for reporting and recording adverse events 
The subject’s parent(s) or legal representative(s) 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 child’s health (since your last visit)?” 
The requirements for recording AEs are detailed in Articles 16 and 17 of the Clinical Trials 
Directive (CTD) 2001/20/EC1 published in 2001, which establishes specific provisions 
regarding the conduct of clinical trials, in particular relating to the implementation of GCP. 
Articles 16 and 17 of the CTD outline the legal obligations for both the Investigator and Sponsor 
for the recording and reporting of all AEs and reactions. 
In line with GCP, from the signing of the ICF, the Investigator will evaluate the subject for 
occurrence of any AEs based on continued observation and medical notes throughout the study. 
Serious AEs, AEs that are considered related to the medicinal (investigational) product, AEs 
leading to discontinuation, BRV infusion site reactions, or AEs considered by the Investigator to 
be critical to the safety evaluation of the protocol will also be recorded on the Adverse Event 
eCRF. Further guidance on the reporting requirements for AEs is provided in Figure 11‒1. The 
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predicted and expected AEs for BRV are also provided in Section 11.1.1.2.1, and reporting 
requirements for serious AEs are detailed in Section 11.1.2.3 . 
 
 
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Figure 11‒1: Adverse event reporting flowchart 
 
AE=adverse event; BRV=brivaracetam; eCRF=electronic case report form; SAE=serious adverse event 
This AE reporting flowchart details the decision-making process for recording AEs in the eCRF. Serious AEs and 
nonserious AEs (that are potentially related to the study drug, result in discontinuation, are considered BRV infusion 
site reactions, or are considered by the Investigator to be critical to the safety evaluation) are to be recorded in the 
eCRF. All AEs will be recorded in the subject’s medical notes. 
Examples of AEs critical to the safety evaluation of the protocol include: 
• 
AEs that might alter the current benefit-risk assessment of BRV use in neonatal seizures 
• 
AEs that would be sufficient to consider changes in the study protocol 
• 
AEs that would be sufficient to consider changes in the overall conduct of the study 
Consent 
AE Occurs 
Record on the subject’s medical notes 
•
Is the AE serious? (see Section 11.1.1.2) 
•
Is the AE a PDILI event that leads to discontinuation? (see Section 11.2.1) 
NO 
Does the AE meet any of the following?  
•
Potentially related to BRV  
•
Results in discontinuation 
•
A BRV infusion site reaction 
•
Considered by the Investigator to be clinically 
relevant to the safety evaluation? 
YES 
Record on eCRF and complete the 
required SAE Report form 
(see Section 11.1.2.3) 
No further action 
required 
Record on eCRF 
NO 
YES 
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11.1.2.1 
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 Investigator’s 
records 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. 
11.1.2.2 
Rule of 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 
11.1.2.3 
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 
parent(s) or legal representative(s) of the need to inform the Investigator of any SAE within this 
period. Serious AEs that the 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. 
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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. 
11.1.2.4 
Immediate reporting of adverse events 
The following AEs must be reported immediately (see Section 11.1.2.3): 
• Serious adverse event (see Section 11.1.1.2):  
− Adverse event that the Investigator classifies as serious by the above definitions 
regardless of causality 
− New onset or worsening of status epilepticus after the administration of BRV 
• Suspected transmission of an infectious agent via a medicinal product (see Section 11.1.4)  
• Adverse event of special interest (see Section 11.1.1.3)  
11.1.3 
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; further details 
regarding follow-up of PDILI events are provided in Section 11.2.1.4.  
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. 
11.1.4 
Suspected transmission of an infectious agent  
A suspected transmission of infectious agent is defined as any infection that is temporally related 
to the administration of the medicinal product with no other likely cause. The Medical Monitor 
should be contacted immediately. No further medicinal product from that specific batch should 
be administered. Infections should be treated according to normal clinical practice. 
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. 
11.1.5 
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. 
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11.1.6 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to BRV so that Investigators, parent(s) or legal representative(s) of the 
clinical study subject, regulatory authorities, and 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. 
No formal interim analysis is planned for this study; however, PK and safety data will be 
presented to and reviewed by a DMC. It was originally planned that the DMC would convene to 
review the PK and safety data every 6 months; however, due to the low enrollment rate, the 
interval between DMC meetings may exceed 6-month intervals, at the discretion of the DMC. 
The DMC will oversee the safety of the study by convening to review the PK and safety data 
after the 6 subjects from the Exploratory Cohort have completed or withdrawn from the study. 
The PK and safety data will again be reviewed after each of the 3 Confirmatory Cohorts 
(12 subjects each) have completed or withdrawn from the study.  
The DMC will consist of 3 voting members, none of whom will be involved in the conduct of the 
study, either by management or participation. As appropriate for the stage of development and 
accumulated experience with BRV, medically qualified personnel at UCB may identify 
additional safety measures (eg, AEs, vital signs, laboratory or heart rate results) for which data 
will be periodically reviewed during the course of the study. 
Serious adverse events and AEs of special interest will be monitored and will be triaged by the 
Study Physician and UCB PS in real time. After this triage, events will be passed on to the DMC 
as appropriate. The DMC or Sponsor can convene an ad hoc DMC meeting to review the data 
and make recommendations on the continuation or modification of the study. The objectives and 
procedures for the DMC will be detailed in the DMC Charter. 
A DMC will be in place for the duration of this study (see Section 13.8.3). 
11.2 
Laboratory measurements 
Safety laboratory assessments will be performed as shown in Table 5‒1, Table 5‒2, and 
Table 5-3. Blood samples will be collected in line with Section 13.2 of the “Ethical 
Considerations for Clinical Trials on Medicinal Products Conducted with the Paediatric 
Population” (European Union Commission ad hoc group, 2008). If clinically significant 
abnormalities are observed, the laboratory measurements may be performed more frequently at 
the Investigator’s discretion. 
Laboratory measurements, including laboratory assessments for PDILI, will be performed by 
local laboratories unless historical data is available. Historical safety laboratory assessments, 
previously collected as standard of care, may be accepted from referring hospitals as Baseline 
measurement if performed 36 hours prior to the Evaluation Period.  
As part of routine assessments performed by local laboratories, the parameters shown in 
Table 11‒1 and Table 11‒2 will be measured. 
 
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Table 11‒1: Mandatory laboratory measurements  
Hematology 
Biochemistry 
Basophils 
Calcium 
Eosinophils 
Chloride 
Lymphocytes 
Potassium 
Atypical lymphocytes 
Sodium 
Monocytes 
Glucose 
Neutrophils 
Urea/BUNa 
Hematocrit 
Creatinineb 
Hemoglobin 
Creatine kinase 
MCH 
AST 
MCHC 
ALT 
MCV 
ALP 
Platelet count 
GGT 
RBC count 
LDH 
WBC count 
Total bilirubin 
 
Direct (conjugated) bilirubin 
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 
a  Urea or BUN to be tested depending on the local lab´s standard panel for neonates. 
b  During the first days of life, creatinine will only be collected if the site assesses this parameter per standard of 
care. 
Table 11‒2: Optional laboratory measurements 
Biochemistry 
Urinalysisb 
Endocrinologyc 
Total cholesterola 
Protein 
TSH 
 
Bacteria 
T4 
 
Glucose 
 
 
pH 
 
 
RBC 
 
 
WBC 
 
RBC=red blood cell; T4=thyroxine; TSH=thyroid-stimulating hormone; WBC=white blood cell 
a Total cholesterol to be measured if this is part of the local lab´s standard panel for neonates. 
b Urinalysis to be performed only if a urine sample was obtained for clinical purposes. A urine dipstick is 
acceptable. 
c TSH and T4 to be recorded for the study only if measured for neonatal screening of congenital hypothyroidism 
prior to or during study participation. 
 
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11.2.1 
Evaluation of PDILI 
The PDILI IMP discontinuation criteria (Food and Drug Administration [FDA], Guidance for 
Industry, Drug-induced liver injury, 2009) for this study are provided in Section 6.3.1, with the 
accompanying required follow-up investigation and monitoring detailed below. All PDILI events 
must be reported as an AE and reported to the study site and Sponsor within 24 hours of learning 
of their occurrence. Any PDILI event that leads to discontinuation must be reported as an AE of 
special interest (see Section 11.1.1.3) and must also be reported as an SAE see Section 11.1.1.2).  
Evaluation of PDILI consists of the diagnostic testing and continued monitoring included in 
Table 11‒3 specific tests dependent on laboratory results and corresponding symptoms) and 
consultation with a local hepatologist (if applicable; discussed in Section 11.2.1.1). Additional 
investigation and monitoring may be required and adapted based on the diagnosis after the cause 
of the liver injury/abnormality is confirmed (details in Section 11.2.1.4).  
The results of all monitoring, including laboratory testing and other testing, should be made 
available to the study site and Sponsor. 
All initial tests resulting in abnormal hepatic laboratory values need to be repeated, but 
appropriate medical action must not be delayed while waiting for the repeat result. 
Table 11‒3 summarizes the required investigations and follow-up for PDILI. 
 
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Table 11‒3: Required investigations and follow-up for PDILI 
Patient 
population 
Laboratory value 
Immediate 
Follow-Up 
 
ALT/ 
AST/ALP 
Direct 
(conjuga-
ted) 
bilirubina 
 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
Subjects 
without 
perinatal 
asphyxia 
≥3xULN 
according to 
the subject’s 
GA and site’s 
normal value 
NA 
Hepatology 
consultation 
(see Section 11.2.1); 
Medical Monitor 
must be notified 
within 24 hours (eg, 
laboratory alert) and 
subject discussed 
with Medical 
Monitor ASAPb 
Immediate, 
permanent IMP 
discontinuation. 
Essential: Must have 
repeat liver chemistry 
values and additional 
testing completed ASAP 
(see Section 11.2.1.1); 
recommended to occur at 
the site with HCP. 
Monitoring of liver 
chemistry values at least 
twice per week until 
values normalize, 
stabilize, or return to 
within Baseline values. 
Subjects 
with 
perinatal 
asphyxiac 
≥5xULN 
according to 
the subject’s 
GA and site’s 
normal value 
NA 
All subjects 
NA 
≥2mg/dL 
ASAP=as soon as possible; GA=gestational age; HCP=healthcare practitioner; IMP=investigational medicinal product; NA=not applicable; PDILI=potential drug-
induced liver injury; ULN=upper limit of normal 
a Any requirement for phototherapy or exchange transfusion due to elevated bilirubin necessitates withdrawal regardless of laboratory values.  
b Details provided in Section 11.2.1.1. The local hepatologist is the expert usually consulted by the treating physician for assessment and management of 
potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist. 
c For subjects with perinatal asphyxia, if initial and peak LFT elevation occurs within 5 days after birth, and if the time course of LFT elevation is compatible 
with hepatic injury due to perinatal asphyxia (ie, peak LFT elevation within few days after birth, and subsequent normalization until up to day 14 after birth): in 
case AST, ALT or ALP elevation ≥5x ULN occurs within 5 days after birth in patients with perinatal asphyxia and suspected hepatic hypoxic injury, study drug 
must be discontinued and LFTs retested within 24 hours. If AST, ALT and ALP values confirmed <5x ULN, the subject may restart study drug after 
consultation with and approval by the Medical Monitor. 
 
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11.2.1.1 
Consultation with Medical Monitor and local hepatologist  
Potential drug-induced liver injury events require notification of the Medical Monitor within 
24 hours, and the subject must be discussed with the Medical Monitor as soon as possible. If 
applicable, the subject may also be discussed with the local hepatologist. The local hepatologist 
is the expert usually consulted by the treating physician for assessment and management of 
potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist 
or neonatologist with relevant expertise. If determined necessary, this discussion should be 
followed by a full assessment (see Section 11.2.1.3) and SAE report (if applicable). 
11.2.1.2 
Immediate action: determination of IMP discontinuation 
All PDILI events require immediate action, testing, and monitoring.  
The immediate action is dependent on the laboratory values and symptoms of hepatitis or 
hypersensitivity and ranges from continuation of IMP (followed by immediate investigation) to 
immediate and permanent discontinuation (see Section 6.3.1 and Table 11‒3 for details). 
When IMP is discontinued, all concomitant medications that are not medically necessary should 
also be discontinued. The Investigator should also consider dose reduction for medically 
necessary concomitant medication and consider changing any medically required concomitant 
medication known to be hepatotoxic to a suitable alternative. 
11.2.1.3 
Testing: identification/exclusion of alternative etiology 
The measurements and additional information recommended for the assessment of PDILI events 
when there is a reasonable possibility that they may have been caused by the IMP are detailed in 
Table 11‒4 (laboratory measurements) and Table 11‒5 (additional information). Recommended 
testing is at the discretion of the Investigator and should be individualized appropriately based on 
clinical situation.  
Results of the laboratory measurements and information collected are to be submitted to the 
Sponsor on the corresponding eCRF. If the medical history of the subject indicates a requirement 
for other assessments not included below, these additional assessments should be completed and 
submitted, as applicable. 
All blood samples will be tested locally. 
Table 11‒4 shows the PDILI laboratory measurements recommended to be assessed.  
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Table 11‒4: Recommended PDILI laboratory measurementsa 
Virology-related 
(virology tests dependent on local vaccination 
schedule) 
HSV blood PCR (or other testing: HSV IgM, 
viral culture of blood or CSF, CSF PCR) 
Enterovirus blood PCR (or other testing) 
Hepatitis A IgM antibodyb 
Hepatitis E IgM antibodyb 
Hepatitis C IgMb 
HBsAgb 
Cytomegalovirus testing (culture or 
polymerase chain reaction) of saliva/urine 
Epstein-Barr viral capsid antigen IgM 
antibody  
Hematology 
Eosinophil count 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
Serum CPK and LDH to evaluate possible 
muscle injury causing transaminase elevation 
Lactate, pyruvate (mitochondrial screen) 
Plasma acylcarnitine profile (fatty acid 
oxidation defects) 
Ferritin (screen for gestational alloimmune 
liver disease [neonatal hemochromatosis]) 
Confirm newborn screening results 
(galactosemia and tyrosinemia) 
Serum amino acid profile (urea cycle and 
metabolic) 
Additional 
Prothrombin time/INR 
CPK=creatine phosphokinase; CSF=cerebrospinal fluid; HBsAg=hepatitis B virus surface antigen; HSV=herpes 
simplex virus; IgM=immunoglobulin M; INR=international normalized ratio; LDH=lactate dehydrogenase; 
PCR=polymerase chain reaction; PDILI=potential drug-induced liver injury 
a Recommended testing is at the discretion of the Investigator and should be individualized appropriately based 
on clinical situation 
b Maternal viral hepatitis status may be considered 
Table 11‒5 shows the additional PDILI information to be collected: 
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Table 11‒5: PDILI information to be collected 
New or updated information 
Concomitant medications prescription with dosages and dates should be included. 
Pertinent medical history, including the following: 
• 
Adverse reactions to drugs 
• 
Allergies 
• 
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin 
deficiency) 
The appearance or worsening of clinical symptoms of hepatitis or hypersensitivity  
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function 
Results of liver imaging or liver biopsy, if done 
Results of any specialist or hepatology consult, if done 
Results of Echocardiogram (for evaluation of potential cardiac dysfunction) and abdominal ultrasound 
with Doppler (vascular and anatomic), if done 
Any postmortem/pathology reports 
PDILI=potential drug-induced liver injury 
11.2.1.4 
Follow-up evaluation 
Potential drug-induced liver injury events require follow-up monitoring as described in 
Table 11‒5. Monitoring should continue until liver chemistry values normalize, stabilize, or 
return to Baseline. Determination of stabilization is at the discretion of the Investigator in 
consultation with the hepatologist (as applicable) and UCB responsible physician, as needed. 
11.3 
Other safety measurements 
11.3.1 
Physical and neurological examinations 
Physical and neurological examinations will be performed at study timepoints described in 
Table 5‒1 and Table 5‒2 for the Exploratory and Confirmatory Cohorts, respectively; and in 
Table 5-3 during the BRV Extension Period and Safety Follow-Up Period for both the 
Exploratory and Confirmatory Cohorts. Physical and neurological examinations will be 
performed by a medically qualified clinician. The physical examinations will include a check for 
the presence of skin rash and skin hypersensitivity.  
Physical and neurological assessments for subjects with HIE will also include the Sarnat scale, a 
classification scale for HIE with grading based on clinical presentation, EEG findings, the 
presence of seizures, and the duration of illness. The Sarnat grading scale comprises 
6 components: alertness, muscle tone, seizures, pupils, respiration, and duration assessed 
together to provide 3 stages (Grade I [mild]; Grade II [moderate]; Grade III [severe]) of HIE 
(Sarnat and Sarnat, 1976). 
Clinically significant new or worsened abnormalities must be reported as AEs. 
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11.3.2 
Medical history including Apgar score 
The Apgar score describes the condition of the newborn infant immediately after birth 
(Papile, 2001) and, when properly applied, is a tool for standardized assessment. It also provides 
a mechanism to record fetal-to-neonatal transition. Apgar score is collected routinely at birth and 
the data will be used as part of the medical history for the subject. 
The Apgar score comprises 5 components: heart rate, respiratory effort, muscle tone, reflex 
irritability, and color, each of which is given a score of 0, 1, or 2. The score is reported at 1 and 
5 minutes after birth. The Apgar score continues to provide convenient shorthand for reporting 
the status of the newborn infant and the response to resuscitation (Committee on Obstetric 
Practice, ACOG; American Academy of Pediatrics; Committee on Fetus and Newborn, ACOG, 
2006). 
11.3.3 
Vital signs 
Vital sign measurements, including systolic blood pressure, diastolic blood pressure, heart rate, 
respiratory rate (including apneas), oxygen saturation (pulse oximetry), and body temperature, 
should be measured at the study timepoints as described in Table 5‒1 and Table 5‒2 for the 
Exploratory and Confirmatory Cohorts, respectively; and in Table 5-3 during the BRV Extension 
Period and Safety Follow-Up Period for both the Exploratory and Confirmatory Cohorts. 
11.3.4 
Biometric parameters 
Biometric parameters, including length, body weight and head circumference, will be measured 
at the study timepoints as described in Table 5‒1 and Table 5‒2 for the Exploratory and 
Confirmatory Cohorts, respectively; and in Table 5-3 during the Safety Follow-Up Period for 
both the Exploratory and Confirmatory Cohorts. Head circumference Baseline measurement 
should be taken within 7 days prior to drug administration, or at birth for subjects ≤7 days old. 
11.3.5 
N-PASS 
The psychometric parameters, including N-PASS, will be measured at the study timepoints as 
described in Table 5‒1 and Table 5‒2 for the Exploratory and Confirmatory Cohorts, 
respectively; and in Table 5-3 during the BRV Extension Period and Safety Follow-Up Period 
for both the Exploratory and Confirmatory Cohorts. 
The N-PASS was developed as a clinically relevant tool to assess ongoing or acute pain in 
neonates and infants, as well as sedation levels. The 5 indicators are: (1) crying/irritability (silent 
cry observed in the intubated infant is scored as a cry), (2) behavior/state, (3) facial expression, 
(4) extremities/tone, and (5) vital signs. Points are added to the preterm infant’s pain score to 
approximate the normal response of a full-term infant. These points were derived from the 
Premature Infant Pain Profile pain assessment tool (Stevens et al, 1996). 
Gestational age groups are <28 weeks (3 points), 28 to 31 weeks (2 points), 32 to 35 weeks 
(1 point), and >35 weeks (0 points). Scores range from 0 to 13. Behavioral state as a modifier 
was not included in the development of N-PASS, as it was designed initially for ongoing pain 
assessment (Hummel et al, 2010). 
11.3.6 
Video-EEG Parameters 
Video-EEG monitoring performed during the Evaluation Period will be assessed for the subject’s 
reactivity, in addition to the interpretation of the N-PASS in terms of sedation status. 
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11.3.7 
HIE (Thompson score) 
The Thompson score will be used to measure the severity of HIE for subjects with HIE at the 
timepoints described in Table 5‒1 and Table 5‒2 for the Exploratory and Confirmatory Cohorts, 
respectively. 
The Thompson score is derived from 9 aspects of the neurological examination of infants with 
HIE: the total score ranges from 0 to 22 and the kappa coefficient is 0.87 (Thompson et al, 
1997). This score allows a more precise description of infants than “mild”, “moderate” or 
“severe” and recognizes the prognostic significance of mixed signs within these 3 categories. In 
normothermic infants, a maximum score >10 during the first 7 days of life predicts an abnormal 
outcome with 100% sensitivity and 61% specificity (Thompson et al, 1997). 
11.3.8 
Withdrawal and rebound phenomena 
Withdrawal and rebound phenomena will be assessed by observing any AEs experienced by 
subjects following the cessation of BRV administration. These AEs will be reported by the 
Investigators, and any AEs relating to BRV withdrawal will be used for the analysis of 
withdrawal and rebound phenomena. Withdrawal and rebound phenomena, if any, will be 
captured from data collected at the end of BRV exposure for subjects in both the Exploratory and 
Confirmatory Cohorts. 
11.3.9 
Mechanical ventilation 
Numbers and percentage of subjects requiring mechanical ventilation will be recorded from 
Baseline through the 48-hour Evaluation Period for the Exploratory Cohort and the 96-hour 
Evaluation Period for the Confirmatory Cohort. 
Duration of mechanical ventilation will be recorded over the Evaluation Period. 
11.3.10 
Bayley Scales of Infant and Toddler Development, Third Edition 
The Bayley-III scales will be used in this study. The data collected will not be used for analysis, 
but as the Baseline for subjects who are entering the long-term study. 
The Bayley-III scales are recognized internationally as one of the most comprehensive 
developmental assessment instruments (Sattler and Hoge, 2006) used to examine the major 
facets of a young child’s development (Bayley, 2006). The Bayley-III scales are a standardized, 
individually administered adaptive assessment that measures the developmental functioning of 
infants and young children from 1 month to 42 months of age (Bayley, 2006). The Bayley-III 
scales measure cognitive, language, motor, social-emotional, and adaptive. 
The Bayley-III scales are an individually administered adaptive assessment that presents children 
with situations and tasks designed to produce an observable set of behavioral responses. They 
consist of a cognitive scale, a language composite scale with receptive and expressive language 
subscales, a motor composite scale with fine and gross motor subscales to be completed by the 
Investigator or designee, a social-emotional scale, comprising social-emotional competence, and 
sensory processing, and an adaptive behavior scale, which assesses the attainment of skills 
necessary for the development of independence, to be completed by the neonate’s parent(s) or 
caregiver. 
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The Bayley-III scales will be completed before the subject enters the long-term study (at EPV 2) 
and again in the long-term study for subjects enrolled in countries where a validated translation 
of the scale is available in the local language.  
12 
STUDY MANAGEMENT AND ADMINISTRATION 
12.1 
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 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, IEC, or Sponsor. 
After implementation of such a measure, the Investigator must notify the Clinical Project 
Manager of the Sponsor within 24 hours and follow any local regulatory requirements. 
12.2 
Monitoring 
Monitoring of the study will be delegated by UCB to a CRO. The CRO will monitor the study to 
meet the CRO’s monitoring Standard Operating Procedures (SOPs), ICH-GCP guideline, and 
applicable regulatory requirements, and to ensure that study initiation, conduct, and closure are 
adequate. 
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, IEC review, and regulatory inspection(s). 
The Investigator will allow UCB (or designee) to periodically review the eCRF entries against 
the 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. 
12.2.1 
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). Printouts of eCRF screens 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 or other printouts, completed scales, quality of life 
questionnaires, or video, for example. Source documents should be kept in a secure, limited 
access area. 
Apart from the VEEG, other source documents that may be computer generated and stored 
electronically must be printed for review by the monitor. Once printed, these copies should be 
signed and dated by the Investigator and become a permanent part of the subject’s source 
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documents. The 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. 
12.2.2 
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 [VEEG], 
laboratory notes). All data reported on the eCRF should be supported by source documents, 
unless otherwise specified in Section 12.2.1. 
12.3 
Data handling 
12.3.1 
Case Report form completion 
The Investigator is responsible for prompt reporting of accurate, complete, and legible data in the 
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 electronic 
eCRF. 
Detailed instructions will be provided in the eCRF Completion Guidelines. 
12.3.2 
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 if the study is performed using electronic data capture. 
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. 
12.3.3 
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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12.4 
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 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 
BRV and other material in accordance with UCB procedures for the study. 
12.5 
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 (Committee for Proprietary Medicinal Products [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. 
12.6 
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 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). 
12.7 
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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by UCB to secure compliance. Continued noncompliance may result in the termination of the 
site’s involvement in the study. 
13 
STATISTICS 
A description of statistical methods follows and will be given in more detail in the Statistical 
Analysis Plan (SAP). In general, descriptive summaries will be used to present the study results 
overall and by cohorts (Exploratory Cohort and each individual Confirmatory Cohort). 
13.1 
Definition of analysis sets 
Analysis sets will be defined as follows: 
• 
The Pharmacokinetic Per-Protocol Set will consist of all subjects who provide at least 
1 measurable plasma sample (with recorded sampling time) on at least 1 post-Baseline visit 
with documented study drug intake times. This analysis set will be used for the Exploratory 
Cohort and the Confirmatory Cohort(s). 
• 
The SS will consist of all enrolled subjects who take at least 1 dose of BRV. All safety 
analyses will be performed on the SS for the Exploratory Cohort and the Confirmatory 
Cohort(s). 
• 
The Full Analysis Set will be used for the analysis of seizure data (efficacy) and will consist 
of all subjects in the SS who have a minimum of 2 hours of interpretable VEEG data from 
both the Baseline period and the first 3 hours of the post-Baseline period after initial BRV 
treatment. 
13.2 
General statistical considerations 
Descriptive statistics, such as the mean, standard deviation, median, 25th percentile, 75th 
percentile, minimum value, and maximum value will be provided for quantitative variables. 
Counts and percentages will be provided for categorical variables. Confidence intervals (CIs) 
(95%) will be provided for efficacy variables, which will be described in the SAP. Key 
supporting data will be provided in data listings. 
13.3 
Pharmacokinetic variable analysis 
The PK data, along with the safety data collected from the Exploratory Cohort and the 
3 Confirmatory Cohorts, will be reviewed by the DMC. In addition, plasma concentrations of 
BRV and its metabolites will be monitored and subjected to interpretation on an ongoing basis. 
The analysis of the PK parameters for the Exploratory and Confirmatory Cohorts will include a 
sub-analysis for any concomitant use of hypothermia. 
13.3.1 
Exploratory Cohort 
Based on the plasma samples collected for the Exploratory Cohort, relevant PK parameters 
including AUC, Cmax, volume of distribution, and clearance, will be estimated using 
noncompartmental methods, with sub-analysis by concomitant use of hypothermia. Clinical 
interpretation of the tolerability of BRV, as well as plasma concentration data from the 
Exploratory Cohort, will be used to confirm, or adjust as needed, the maximum recommended 
dose for the Confirmatory Cohorts.  
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13.3.2 
Confirmatory Cohorts 
Plasma concentrations of BRV will be used as described for the PK Exploratory Cohort together 
with demographic and other variables, to build a population PK model by nonlinear mixed 
effects modeling. The model will be used for simulating various dosing regimens to establish 
dosing recommendations as a function of developmental variables. Details of the population PK 
modeling procedures will be described in a separate Data Analysis Plan. 
13.4 
Safety analyses 
All safety analyses will be presented for the SS. Descriptive summaries will be presented by 
cohort for AEs, SAEs, physical and neurological examination assessments, laboratory results, 
heart rate, vital signs, body weight, and head circumference. Subject characteristics related to 
safety, such as cooling status variables (target low body temperature, age since birth when 
cooling began, duration of cooling [date and start and stop time of cooling], and timing of 
cooling in relation to first dose of BRV), rewarming status variables (duration of rewarming 
[date and start and stop time of rewarming] and timing of rewarming in relation to first dose of 
BRV), the mother’s use of AEDs (including BZD and opiates) at childbirth, N-PASS score, and 
Thompson score will also be summarized descriptively. The primary cause of seizure (eg, HIE, 
hemorrhage, or infarction; CNS malformations; CNS infections; undetermined causes) may also 
be used to categorize the safety review. EEG parameters for the assessment of sedation will also 
be summarized. 
13.5 
Planned efficacy analyses 
All efficacy parameters will be summarized descriptively. 
Video-EEGs will be assessed locally by the Investigator for any medical decisions or medical 
interventions. Video-EEGs may also be assessed by a blinded, central reader to support 
Investigators if needed. The final analysis of VEEG outputs will be based solely on the 
assessment of a central reader. Efficacy parameters will be summarized descriptively (overall 
[with CIs]) by cohort. All efficacy variables will be analyzed by the primary cause of seizure 
(HIE, hemorrhage, or infarction; CNS malformations; CNS infections; undetermined causes) and 
concomitant use of hypothermia, and reported for each subject using data listings.  
13.5.1 
Analysis of the secondary efficacy variables 
The main secondary efficacy variable is as follows: 
• Proportion of responders to BRV treatment from Baseline to 3 hours after the initial BRV 
dose.  
A BRV responder is defined as a subject who achieves the following reduction in seizure 
burden (ENS in minutes per hour) without need for rescue medication, compared to the 
seizure burden measured during the Baseline Period immediately prior to BRV 
administration, evaluated for a 2-hour period starting 1 hour after the start of initial BRV 
treatment: 
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− At least 80% reduction in nonsevere seizure burden 
(Nonsevere seizure burden is defined as ≤50% seizure activity on VEEG in all 30-minute 
timespans) 
OR 
− At least 50% reduction in severe seizure burden 
(Severe seizure burden is defined as >50% seizure activity on VEEG in any 30-minute 
timespan). Timespans of 30 minutes refer to the following intervals within the 2-hour 
period: 0 to ≤30 minutes, >30 to ≤60 minutes, >60 to ≤90 minutes, and >90 to ≤120 
minutes. 
For this study, an ENS is defined as an EEG seizure lasting for at least 10 seconds on VEEG. 
Baseline seizure burden is defined as seizure burden measured on the continuous VEEG (total 
ENS in minutes per hour) during a period of up to 1 hour immediately prior to the first 
administration of study drug. 
For the Confirmatory Cohorts this means: 
• For the analysis of the main secondary efficacy variable, subjects must not have used any 
rescue medication for the treatment of ENS during the first 3 hours after initiation of BRV 
treatment to be considered BRV responders.  
• For the analysis of the secondary efficacy variables (other than the main secondary efficacy 
variable) and other efficacy variables, subjects must not have used any rescue medication for 
the treatment of ENS following the first 3 hours after initiation of BRV treatment to be 
considered BRV responders. 
Additional details will be provided in the SAP. 
Descriptive statistics will be presented for the following secondary efficacy variables: 
• Proportion of subjects with at least 80% reduction in nonsevere seizure burden from Baseline 
to 3 hours after the initial BRV treatment 
• Proportion of subjects with at least 50% reduction in severe seizure burden from Baseline to 
3 hours after the initial BRV treatment 
• Absolute reduction in average seizure burden measured by continuous VEEG from Baseline 
to the end of the 96-hour Evaluation Period 
• Percent reduction in average seizure burden measured by continuous VEEG from Baseline to 
the end of the 96-hour Evaluation Period 
• Proportion of BRV responders at the end of the 96-hour Evaluation Period 
• Proportion of subjects who are seizure-free (100% reduction in seizure burden from 
Baseline) at 24 hours following the start of initial BRV treatment, categorized by subjects 
with nonsevere or severe seizure burden at Baseline 
• Time to reduction in seizure burden for BRV responders (defined as the first timepoint when 
BRV responder criteria are met) 
• Seizure freedom at the end of the Down-Titration Period (Confirmatory Cohorts only) 
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• Rate of at least 50% reduction in ENS frequency per hour from Baseline to the end of the 
96-hour Evaluation Period 
• Proportion of subjects who are seizure-free by time interval at 3 hours, at 3-hour intervals 
thereafter through 24 hours, and every 12 hours to 24 hours following the start of the initial 
BRV treatment 
• Absolute difference in clinical seizures at the end of the 24-hour Evaluation Period from 
Baseline for neonates with motor seizures at the time of inclusion 
• Percent difference in clinical seizures at the end of the 24-hour Evaluation Period from 
Baseline for neonates with motor seizures at the time of inclusion  
Historical controls will be matched by age and condition, using comparable standard of care and 
diagnostic methods. The efficacy of BRV will be evaluated for the main efficacy variable by 
comparing the 95% CI of the BRV responder rate (with all Confirmatory Cohorts combined) to 
responder rates for the referenced historical control group. If the BRV lower 95% CI limit is 
higher than the historical control group responder rate, then BRV would be considered 
efficacious compared to the historical control group. If the BRV upper 95% CI limit is lower 
than the historical control group responder rate, then BRV will not be considered efficacious 
compared to the historical control group. If the BRV 95% CI limits contain the historical control 
group responder rates, then the results will be considered inconclusive.  
13.5.2 
Analysis of the other efficacy variables 
Descriptive statistics will be presented for the other efficacy variables: 
• Absolute reduction from Baseline in seizure burden at evaluation periods of 0 hours to 
3 hours, >3 hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, >24 hours to 
36 hours, >36 hours to 48 hours, >48 hours to 72 hours, and >72 hours to 96 hours after the 
start of initial BRV treatment 
• Percentage reduction from Baseline in seizure burden at evaluation periods of 0 hours to 
3 hours, >3 hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, >24 hours to 
36 hours, >36 hours to 48 hours, >48 hours to 72 hours, and >72 hours to 96 hours after the 
start of initial BRV treatment 
• Categorized percentage reduction from Baseline to the end of the 96-hour Evaluation Period 
in seizure burden (<-25% [worsening], -25% to <25% [no change], 25% to <50%, 50% to 
<80%, and ≥80%) 
• Proportion of BRV responders by time interval at evaluation periods of 0 hours to 3 hours, 
>3 hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, >24 hours to 36 hours, 
>36 hours to 48 hours, >48 hours to 72 hours, and >72 hours to 96 hours after the start of 
initial BRV treatment 
• Proportion of subjects who are switched over from BRV to another AED during the 96-hour 
Evaluation Period 
• Proportion of responders to other treatment during the 96-hour Evaluation Period (including 
at the end of the 96-hour Evaluation Period, and by time intervals: 0 hours to 3 hours, 
>3 hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, >24 hours to 36 hours, 
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>36 hours to 48 hours, >48 hours to 72 hours, and >72 hours to 96 hours after the start of 
initial BRV treatment 
(A responder to other treatment is defined as at least 80% reduction in nonsevere seizure 
burden from start of other treatment to end of other treatment or at least 50% reduction in 
severe seizure burden from the initiation of other treatment to end of other treatment during 
the 96-hour Evaluation Period). 
13.6 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol that could potentially have a 
meaningful impact on key PK, efficacy, or safety outcomes for an individual subject. The criteria 
for identifying important protocol deviations and the classification of important protocol 
deviations will be documented in a protocol-defined specification document. To the extent 
feasible, rules for identifying important protocol deviations will be defined without review of the 
data and without consideration of the frequency of occurrence of such deviations. Whenever 
possible, criteria for identifying important protocol deviations will be implemented 
algorithmically to ensure consistency in the classification of important protocol deviations across 
all subjects. 
Important protocol deviations will be reviewed as part of the ongoing data cleaning process prior 
to database lock to confirm exclusion from analysis sets. 
13.7 
Handling of dropouts or missing data 
For subjects who dropped out during the Evaluation Period, the number of hours from the start of 
the Evaluation Period to the time of withdrawal (in hours) will be considered for analysis. 
Subjects in the Confirmatory Cohorts who started another AED, increased the dose or frequency 
of administration of an AED ongoing at the time the first BRV infusion started, or are switched 
to another AED, or have been administered any rescue medication for the treatment of ENS 
during the first 3 hours after initiation of BRV treatment will be considered BRV nonresponders.  
The impact of missing data on the assessment of the main secondary efficacy variable will be 
evaluated with sensitivity analyses with further details to be included in the SAP.  
No imputation of missing values associated with an individual date or visit is planned for the 
safety analysis, with the exception of partial date information for AEs and concomitant 
medications, in order to determine whether they are treatment emergent. 
13.8 
Planned PK data review and safety data monitoring 
13.8.1 
Exploratory Cohort 
Upon the completion of the Exploratory Cohort, the DMC will be provided with the summaries 
and the listings of PK and safety data for review to make recommendations concerning the 
dosing of BRV in the Confirmatory Cohorts (see Section 13.8.3). During the DMC review of PK 
and safety data, the enrollment of subjects will be on hold. 
13.8.2 
Confirmatory Cohorts 
At least 36 subjects will be enrolled in 3 consecutive Confirmatory Cohorts, each consisting of 
12 subjects. A PK and safety data review will be performed after completion each of the cohorts. 
Both PK and safety summaries and data listings will be generated first for the DMC to review. In 
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addition, plasma concentrations of BRV and its metabolites will be monitored and subjected to 
interpretation on an ongoing basis. 
During the DMC review of the PK and safety data, the recruitment of subjects for the subsequent 
Confirmatory Cohorts will continue. The DMC may give a recommendation to stop the study 
after reviewing the PK and safety data. 
13.8.3 
DMC and stopping rules 
The DMC will consist of 3 voting members, none of whom will be involved in the conduct of the 
study, either by management or participation.  
The DMC will oversee the PK and safety of the study by reviewing the PK and safety data 
periodically, in order to evaluate the risk-benefit profile in relation to the overall progress of the 
study. The DMC will make recommendations regarding subject safety and continuance of the 
study based on the observed risk-benefit of the emerging data; however, no formal statistical 
stopping rules will be defined. Details will be provided in a DMC charter. 
13.9 
Determination of sample size 
At least 42 evaluable subjects will be enrolled in this study. At least 6 subjects will be enrolled in 
the Exploratory Cohort and at least 36 subjects will be enrolled in 3 successive Confirmatory 
Cohorts, each consisting of 12 subjects. At least 2 subjects undergoing hypothermia treatment 
will be included in the Exploratory Cohort and each of the 3 Confirmatory Cohorts. 
Subjects in the Exploratory Cohort might be replaced due to lack of data, as deemed necessary 
following the review of PK and safety data by the DMC. 
No formal sample size calculation has been performed as a single treatment BRV arm is planned 
for descriptive summary of results and for comparison with the 6 subjects from the Exploratory 
Cohort. The total number of at least 36 subjects in the Confirmatory Cohorts is expected to 
provide sufficient evidence of tolerability, safety, and efficacy, as well as good precision for the 
PK profile of BRV in neonates. 
Subjects who drop out or are withdrawn from study participation will not be replaced. 
14 
ETHICS AND REGULATORY REQUIREMENTS 
14.1 
Informed consent 
The informed consent of the parent(s) or legal representative(s) for the subject 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. 
When a neonate with repeated EEG seizures is identified, the parent(s) or legal representative(s) 
will be approached and given written information about the underlying disease and a basic 
description of the study. This information will be discussed with the parent(s) or legal 
representative(s). If the parent(s) or legal representative(s) of the subject are interested in study 
participation, the approved ICF will be provided to them, and they will be given time to read the 
document. Prior to obtaining informed consent, information should be given in both oral and 
written form in a language and at a level of complexity understandable to the subject’s parent(s) 
or legal representative(s), by the Investigator (or designee). The parent(s) or legal 
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representative(s) of each subject will have the opportunity to discuss the study and its 
alternatives with the Investigator.  
Prior to participation in the study, the ICF must be signed and personally dated by the subject’s 
parent(s) or legal representative(s), and by the person who conducted the informed consent 
discussion (Investigator or designee). The subject’s parent(s) or legal representative(s) must 
receive a copy of the signed and dated ICF. As part of the consent process, the parent(s) or legal 
representative(s) of each subject must consent to direct access to the subject’s medical records 
for study-related monitoring, auditing, IEC review, and regulatory inspection. An informed 
consenting process managed via telephone is allowed where applicable per local regulations. 
During the Screening, Baseline, Evaluation, and BRV Extension Periods, continuous consent 
will be ensured by meetings between the Investigator and/or designee and the parent(s) or legal 
representative(s). The purpose of these meetings will be to discuss the ongoing care of the 
subject, as well as their continued participation in the study. Parent(s) or legal representative(s) 
will be informed again that they can withdraw the subject from the study at any time and that the 
decision will not influence the care of the subject. Continuous consent will be documented in the 
subjects’ medical charts and eCRF. Comprehension of the study and its potential risks is 
enhanced by this continuous process (Allmark and Mason, 2006) and, thus, a more informed 
consent is obtained. 
If the ICF 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 ICF by 
the IEC and use of the amended form. 
14.2 
Subject identification cards 
Upon signing the ICF, the subject’s parent(s) or legal representative(s) will be provided with a 
subject identification card of his/her neonate in the language of the subject’s parent(s) or legal 
representative(s). The Investigator will fill in the subject identifying information and medical 
emergency contact information. The Investigator will instruct the subject’s parent(s) or legal 
representative(s) to keep the card with him/her at all times. 
14.3 
Independent Ethics Committees 
The study will be conducted under the auspices of an 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 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, ICF, IB, 
Investigator’s curriculum vitae (if applicable), advertisement (if applicable), and all other 
subject-related documents to be used for the study to the IEC for its review and approval. 
Before initiating the study, the Investigator will have written and dated full approval from the 
IEC responsible for the protocol. 
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The Investigator will also promptly report to the 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 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 IEC as allowed. 
As part of the IEC requirements for continuing review of approved studies, the Investigator will 
be responsible for submitting periodic progress reports to the IEC (based on IEC 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 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 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 IEC notification. 
14.4 
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 
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). 
14.5 
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 IEC, and the regulatory authorities (if required), prior to being 
implemented. 
15 
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. 
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16 
REFERENCES 
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children. Clin Pharmacol Ther. 2015;98:288-97. 
Allmark P, Mason S. Should desperate volunteers be included in randomised controlled trials? J 
Med Ethics. 2006;32:548-53. 
Bayley N. Bayley Scales of Infant and Toddler Development. 3rd ed. San Antonio: Pearson 
Education Inc; 2006. 
Boylan GB, Rennie JM, Chorley G, Pressler RM, Fox GF, Farrer K et al. Second-line 
anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study. Neurology. 
2004;62:486-8. 
Boylan GB, Rennie JM, Pressler RM, Wilson G, Morton M, Binnie CD. Phenobarbitone, 
neonatal seizures, and video-EEG. Arch Dis Child Fetal Neonatal Ed. 2002;86:F165-70. 
Castro Conde JR, Hernández Borges AA, Doménech Martínez E, González Campo C, Perera 
Soler R. Midazolam in neonatal seizures with no response to phenobarbital. Neurology. 
2005;64:876-9. 
Clancy RR, Legido A, Lewis D. Occult neonatal seizures. Epilepsia. 1988;29:256-61. 
Committee on Obstetric Practice, ACOG; American Academy of Pediatrics; Committee on Fetus 
and Newborn, ACOG. ACOG Committee Opinion. Number 333, May 2006 (replaces No. 174, 
July 1996): The Agpar score. Obstet Gynecol. 2006;107:1209-12. 
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002. 
European Union Commission ad hoc group. Recommendations of the ad hoc group for the 
development of implementing guidelines for Directive 2001/20/EC relating to good clinical 
practice in the conduct of clinical trials on medicinal products for human use. Ethical 
Considerations for Clinical Trials on Medicinal Products Conducted with the Paediatric 
Population. 2008; 13.2. https://ec.europa.eu/health/sites/health/files/files/eudralex/vol-
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Glass HC, Kan J, Bonifacio SL, Ferriero DM. Neonatal seizures: treatment practices among term 
and preterm infants. Pediatr Neurol. 2012;46:111-5. 
Hummel P, Lawlor-Klean P, Weiss MG. Validity and reliability of the N-PASS assessment tool 
with acute pain. J Perinatol. 2010;30:474-8. 
Jullien V, Pressler RM, Boylan G, Blennow M, Marlow N, Chiron C, et al. Pilot evaluation of 
the population pharmacokinetics of bumetanide in term newborn infants with seizures. J Clin 
Pharmacol. 2015;56:284-90 
Leroux S, Turner MA, Barin-Le Guellec C, Hills H, van den Ankers JN, Kearns GL, et al. 
Pharmacokinetic Studies in Neonates: The Utility of an Opportunistic Sampling Design. Clin 
Pharmacokinet. 2015;54:1273–85.  
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Mizrahi E, Kellaway P. Characterization and classification of neonatal seizures. Neurology. 
1987;37:1837-44. 
O’Hara K, Wright IM, Schneider JJ, Jones AL, Martin JH. Pharmacokinetics in neonatal 
prescribing: evidence base, paradigms and the future. 2015;80:1281-8. 
Painter MJ, Scher MS, Stein AD, Armatti S, Wang Z, Gardiner JC, et al. Phenobarbital 
compared with phenytoin for the treatment of neonatal seizures. N Engl J Med. 1999;341:485-9. 
Papile LA. The Apgar score in the 21st century. N Engl J Med. 2001;344:519-20. 
Pressler RM, Mangum B. Newly emerging therapies for neonatal seizures. Semin Fetal Neonatal 
Med. 2013;18:216-23 
Pressler RM, Boylan GB, Marlow N, Blennow M, Chiron C, Cross JH. Bumetanide for the 
treatment of seizures in newborn babies with hypoxic ischaemic encephalopathy (NEMO): an 
open-label, dose finding, and feasibility phase 1/2 trial. Lancet Neurol. 2015;14:469-77. 
Ronen GM, Penney S, Andrews W. The epidemiology of clinical neonatal seizures in 
Newfoundland: a population-based study. J Pediatr. 1999;134:71-5. 
Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and 
electroencephalographic study. Arch Neurol. 1976;33:696-705. 
Sattler JM, Hoge RD. Assessment of children: behavioral, social, and clinical foundations. Fifth 
ed. La Mesa: Jerome M Sattler; 2006. 
Scher MS, Alvin J, Gaus L, Minnigh B, Painter MJ. Uncoupling of EEG-clinical neonatal 
seizures after antiepileptic drug use. Pediatr Neurol. 2003;28:277-80. 
Slaughter L, Patel AD, Slaughter JL. Pharmacological treatment of neonatal seizures: a 
systematic review. J Child Neurol. 2013;28:351-64. 
Stevens B, Johnston C, Petryshen P, Taddio A. Premature Infant Pain Profile: development and 
initial validation. Clin J Pain. 1996;12:13-22. 
Thompson CM, Puterman AS, Linley LL, Hann FM, van der Elst CW, Molteno CD, et al. The 
value of a scoring system for hypoxic ischaemic encephalopathy in predicting 
neurodevelopmental outcome. Acta Paediatr. 1997;86:757-61. 
Tulloch JK, Carr RR, Ensom MA. A systematic review of the pharmacokinetics of antiepileptic 
drugs in neonates with refractory seizures. J Pediatr Pharmacol Ther. 2012;17:31-44. 
van Rooij LG, van den Broek MP, Rademaker CM, de Vries LS. Clinical Management of 
Seizures in Newborns: diagnosis and management. Paediatr Drugs. 2013a;15:9-18. 
van Rooij LG, Hellström-Westas L, de Vries LS. Treatment of neonatal seizures. Semin Fetal 
Neonatal Med. 2013b;18:209-15. 
Volpe J. Neurology of the newborn. Fifth ed. Philadelphia: Saunders Elsevier; 2008. 
Weeke LC, Toet MC, van Rooij LG, Groenendaal F, Boylan GB, Pressler RM, et al. Lidocaine 
response rate in aEEG-confirmed neonatal seizures: Retrospective study of 413 full-term and 
preterm infants. Epilepsia. 2016;57(2):233-42. 
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Zhao W, Hill H, Le Guellec C, Neal T, Mahoney S, Paulus S, et al. Population pharmacokinetics 
of ciprofloxacin in neonates and young infants less than three months of age. Antimicrob Agents 
Chemother. 2014;58(11):6572-80. 
Zhao W, Jacqz-Aigrain E. Author’s reply to Standing et al. Pharmacokinetic studies in neonates: 
the utility of an opportunistic sampling design. Clin Pharmacokinet. 2015;54:1289-91. 
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17 
APPENDICES 
17.1 
Protocol Amendment 1 
Rationale for the amendment 
The primary purpose of this non-substantial amendment is to make LFT ranges specified in the 
exclusion and withdrawal criteria, as well as the PDILI criteria, required investigations and 
laboratory measurements more age specific and appropriate for the target patient population. 
Changes were also made to take into account feedback from investigators on the practical aspects 
of conducting a clinical study in the neonatal population. In addition, editorial changes were 
made to the text in order to clarify different aspects of the study design. Administrative changes 
may not be included in the summary table of changes since they are considered minor. 
Modifications and changes 
Global changes 
• Duration of BRV infusion was specified 
• Condition under which BRV treatment should be stopped after a subject completed the 
Evaluation Period was clarified. 
• The Schedule of Assessment was adapted to reflect protocol changes 
• Drug dosing diary was introduced for subjects treated with oral BRV at home during the 
BRV Extension 
• Duration of VEEGs performed during the Down-Titration Period was specified 
• Exclusion criterion #7 was modified: AST, ALT and ALP values were specified for subjects 
with perinatal asphyxia 
• Numbering of “may” withdrawal criteria” was changed to a consecutive numbering 
throughout section 6.3 
• Withdrawal criterion #6 was modified: AST, ALT and ALP values were specified for 
subjects with perinatal asphyxia 
• Withdrawal criterion #9a was modified (former “may” withdrawal criterion #3): AST, ALT 
and ALP values were specified for subjects with perinatal asphyxia 
• PDILI criterion was aligned with updated exclusion criterion#7, withdrawal criterion #6 and 
withdrawal criterion #9a (former “may” withdrawal criterion #3) 
• Type of syringes used to administer oral BRV during the BRV Extension Period was aligned 
with those used in Follow-up study N01266 
• Timepoint of EPV2 was specified 
• Method of PK blood sample collection was specified 
• Description of AESI associated with PDILI was aligned with the updated PDILI criterion 
• Reporting requirements for PDILI were clarified 
• Number of DMC voting members was increased from 3 to 4 members 
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• Consultation with local hepatologists was modified in case of PDILI 
• Description of the testing, laboratory measurements, information to be collected, and 
investigation of PDILI was modified  
• PDILI laboratory measurements were added to cover additional potential causes of PDILI in 
neonates 
 
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Specific changes 
Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Sections 
2.3, 5.1.1, 
5.4.2, 7.2 and 
8.1.3 
Intravenously administered BRV is 
bioequivalent to the same dosage 
given orally in healthy adults when 
given as a bolus or as a 15-minute 
infusion 
Intravenously administered BRV is 
bioequivalent to the same dosage given 
orally in healthy adults when given as 
a bolus or as an approximately 15-
minute infusion 
Based on Investigators´ feedback, the duration 
of infusions was adapted to clinical needs.  
Sections 
5.1.2, 8.2.3 
and Footnote 
to Table 5-2 
If subjects continue to have seizures 
after 96 hours of BRV 
administration, BRV administration 
will be stopped and replaced by 
another AED. 
If subjects do not benefit from BRV 
treatment after 96 hours of BRV 
administration, BRV administration 
will be stopped and replaced by 
another AED 
Condition clarified under which BRV treatment 
should be stopped after a subject completed the 
Evaluation Period. 
Table 5-1 
MDZ infusion 
Removed 
MDZ treatment removed as it is not considered 
a study specific assessment but standard of 
care. 
Tables 5-1 
and 5-2 
Not applicable 
Dispense BRV dosing diary 
  
Dosing diary added to allow parents to 
document the dosing of BRV during the BRV 
Extension Period, if oral BRV is administered 
at home. 
Footnote to 
Table 5-1  
Not applicable 
The BRV dosing diary will be 
dispensed only if the subject enters the 
BRV Extension Period 
Index j added for clarification of the newly 
inserted item “Dispense BRV dosing diary”. 
Footnote to 
Table 5-2 
Not applicable 
The BRV dosing diary will be 
dispensed only if the subject enters the 
BRV Extension Period 
Index l added for clarification of the newly 
inserted item “Dispense BRV dosing diary”. 
Table 5-3 
Not applicable 
Review BRV dosing diary 
Task added, which is part of the Investigators´ 
drug accountability. 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Table 5-3 
VEEG 
1-hour VEEG 
The duration of video-EEGs recorded during 
Down-Titration was specified to clearly 
separate this assessment from the 24-hour 
continuous video-EEG performed during the 
Evaluation Period. 
Footnote to 
Table 5-3 
Video-EEG will only apply to 
subjects of the Confirmatory 
Cohorts who complete the study 
after the Evaluation Period. 
Video-EEG will only apply to subjects 
of the Confirmatory Cohorts who 
complete the study after the Evaluation 
Period. The video-EEG will be 
recorded for at least 1 hour on the final 
day of the Down-Titration Period. 
Additional video-EEGs can be 
performed at any time during the 
Down-Titration Period at the 
investigator´s discretion. 
Description of the video-EEG that will be 
recorded at the end of the Down-Titration 
Period was specified to clearly separate this 
assessment from the 24-hour continuous video-
EEG performed during the Evaluation Period. 
Also, adding clarification that the protocol 
allows other video-EEGs to be performed 
during the Down-Titration Period at the 
discretion of the Investigator. 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 6.2 
7. Subject has 2x upper limit of 
normal (ULN) of any of the 
following: aspartate 
aminotransferase (AST), alanine 
aminotransferase (ALT), and 
alkaline phosphatase (ALP), 
according to the subject’s GA 
and the site’s normal range 
values for the respective GA. 
7a. Subject has 2x upper limit of 
normal (ULN) of any of the 
following: aspartate 
aminotransferase (AST), alanine 
aminotransferase (ALT), and 
alkaline phosphatase (ALP), with 
the following exception:  
 
For subjects with perinatal 
asphyxia, elevation of AST, ALT 
or ALP <5x ULN is acceptable, if 
initial and peak elevation of liver 
function tests (LFTs) occurs 
within 5 days after birth, and the 
time course of LFT elevation is 
compatible with hepatic injury due 
to perinatal asphyxia.  
 
The determination of ULN will be 
based on the subject's GA and the 
site’s normal range values for the 
respective GA. 
Based on Investigators´ feedback, LFT values 
specified were modified to make them more 
age and indication specific. These changes are 
also intended to ensure a balanced enrollment 
of subjects, regardless of the cause/underlying 
disease of ENS. 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 6.3 
6. Subject has 3x ULN of any of 
the following: AST, ALT, and 
ALP, according to the subject’s 
GA and the site’s normal range 
values for the respective GA. 
6a. Subject has AST, ALT or ALP 
values 3x ULN, with the following 
exception: 
 
For subjects with perinatal 
asphyxia, elevation of AST, ALT 
or ALP <5x ULN is acceptable for 
continuation in the study, if initial 
and peak elevation of LFTs occurs 
within 5 days after birth, and if the 
time course of LFT elevation is 
compatible with hepatic injury due 
to perinatal asphyxia (ie, peak 
LFT elevation within a few days 
after birth, and subsequent 
normalization until up to day 14 
after birth). 
 
In case AST, ALT or ALP 
elevation ≥5x ULN occurs within 
5 days after birth, study drug must 
be discontinued and LFTs retested 
within 24 hours. If AST, ALT and 
ALP are confirmed to be <5x 
ULN, the subject may restart study 
drug after consultation with and 
approval by the Medical Monitor. 
 
The determination of ULN will be 
based on the subject's GA and the 
site’s normal range values for the 
respective GA. 
Based on Investigators´ feedback, LFT values 
specified in withdrawal criterion #6 were 
adapted in accordance with exclusion criteria 
changes (see Section 6.2).  
 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 6.3 
1. Subject experiences prolongation 
of seizure duration, a worsening 
of seizure burden, or emergence 
of new seizure type or illness 
considered by the investigator to 
require intervention. 
7a. Subject experiences prolongation 
of seizure duration, a worsening 
of seizure burden, or emergence 
of new seizure type considered by 
the investigator to require 
intervention.  
Modified to delete redundant information 
which is covered by withdrawal criterion #8. 
Numbering changed to a consecutive 
numbering throughout section 6.3. 
 
Section 6.3 
2. Investigator may withdraw 
subject due to any medical 
condition, based on clinical 
judgment and discretion. 
8.  Investigator may withdraw 
subject due to any medical 
condition, based on clinical 
judgment and discretion. 
Numbering changed to a consecutive 
numbering throughout section 6.3. 
Section 6.3 
3. The Investigator may withdraw 
the subject if AST/ ALT/ ALP 
levels are between >2x and 
3x ULN, according to the 
subject’s GA and the site’s 
normal range values for the 
respective GA. 
9a. Subject has AST, ALT or ALP 
values between >2x and 
≤3x ULN, with the following 
exception:  
For subjects with perinatal 
asphyxia, elevation of AST, ALT 
or ALP <5x ULN is acceptable 
for continuation in the study, if 
initial and peak LFT elevation 
occurs within 5 days after birth, 
and if the time course of LFT 
elevation is compatible with 
hepatic injury due to perinatal 
asphyxia (ie, peak LFT elevation 
within a few days after birth, and 
subsequent normalization until up 
to day 14 after birth). 
The determinations of ULN will 
be based on the subject’s GA and 
the site’s normal range values for 
the respective GA. 
Aligned with changes to exclusion criterion #7 
and withdrawal criterion #6.  
Numbering changed to a consecutive 
numbering throughout section 6.3. 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 6.3 
4. Subject has rapidly increasing 
total bilirubin without requiring 
or being expected to require 
phototherapy or exchange 
transfusion; the subject’s 
withdrawal will be at the 
discretion of the Investigator. 
10. Subject has rapidly increasing 
total bilirubin without requiring 
or being expected to require 
phototherapy or exchange 
transfusion; the subject’s 
withdrawal will be at the 
discretion of the Investigator. 
Numbering changed to a consecutive 
numbering throughout section 6.3. 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 6.3.1 
Subject has AST/ALT/ALP values 
>3x ULN according to the subject’s 
GA and the site’s normal values for 
that GA. 
Subject has AST, ALT or ALP values 
>3x ULN, with the following 
exception: 
For subjects with perinatal asphyxia, 
elevation of AST, ALT or ALP 
<5x ULN is acceptable for 
continuation in the study, if initial and 
peak LFT elevation occurs within 
5 days after birth, and if the time 
course of LFT elevation is compatible 
with hepatic injury due to perinatal 
asphyxia (ie, peak LFT elevation 
within few days after birth, and 
subsequent normalization until up to 
day 14 after birth).  
In case AST, ALT or ALP elevation 
≥5x ULN occurs within 5 days after 
birth, study drug must be discontinued 
and LFTs retested within 24 hours. If 
AST, ALT and ALP are confirmed to 
be <5x ULN, the subject may restart 
study drug after consultation with and 
approval by the Medical Monitor. 
The determination of ULN will be 
based on the subject's GA and the 
site’s normal range values for the 
respective GA. 
The PDILI criterion was aligned with changes 
to exclusion criterion #7, withdrawal 
criterion#6 and withdrawal criterion #9a 
(former “may” withdrawal criterion #3). 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 7.2  
For subjects who are switched to 
BRV oral solution, the dose will be 
measured using the appropriate 
syringes (1mL and 5mL) with an 
adaptor able to fit all the bottle 
sizes.  
For subjects who are switched to BRV 
oral solution, the dose will be 
measured using the appropriate 
syringes (1mL, 3mL or 10mL) with an 
adaptor able to fit all the bottle sizes.  
To avoid confusion and the risk of dosing 
errors in subjects transitioning to Follow-up 
study N01266, syringes used for the 
administration of oral BRV were aligned with 
those used in study N01266. 
Section 7.3 
Brivaracetam 10mg/mL oral 
solution will be packaged in 300mL 
type-III amber glass bottles with 
child-resistant tamper evident 
polypropylene screw closures. 
Syringes of 1mL and 5mL will be 
provided with an adaptor able to fit 
all the bottle sizes. 
Brivaracetam 10mg/mL oral solution 
will be packaged in 300mL type-III 
amber glass bottles with child-resistant 
tamper evident polypropylene screw 
closures. Syringes of 1mL, 3mL or 
10mL will be provided with an adaptor 
able to fit all the bottle sizes. 
To avoid confusion and the risk of dosing 
errors in subjects transitioning to Follow-up 
study N01266, syringes used for the 
administration of oral BRV were aligned with 
those used in study N01266. 
Sections 7.7 
and 8.1.4 
Not applicable 
Hand out and return of a dosing diary 
and documentation of drug use during 
home administration of oral BRV 
added to the description of the BRV 
Extension Period (EPV1, EPV2) 
Introduction of a dosing diary to facilitate 
parents´ recording of BRV oral solution 
administered at home during the BRV 
Extension Period. Diaries will be returned to 
the site and reviewed by the site personnel to 
ensure correct use/dosing of BRV. 
Section 7.8.2 
For the Exploratory Cohort, with 
the exception of MDZ as scheduled 
in the Protocol, if other BZDs are 
given prior to the first BRV 
administration, the subjects will be 
considered BRV nonresponders. 
Removed 
The Exploratory Cohort will not be analyzed 
for efficacy. For this reason it is unreasonable 
to classify subjects as “BRV nonresponders”. 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 7.8.3 
For the analysis of the key efficacy 
variables, subjects must not have 
used >1 dose of rescue medication 
following the first 3 hours after 
initiation of BRV treatment to be 
considered BRV responders.  
For the analysis of the key efficacy 
variables (other than the main efficacy 
variable) and other efficacy variables, 
subjects must not have used >1 dose of 
rescue medication following the first 3 
hours after initiation of BRV treatment 
to be considered BRV responders.  
Modified to clarify what is meant by the term 
“key efficacy variables”. 
Section 8.1.4 
Not applicable 
In this case the parent(s) or legal 
representative(s) will receive a dosing 
diary to record the home 
administration of oral BRV. 
Introduction of a dosing diary to facilitate 
parents´ recording of BRV oral solution 
administered at home during the BRV 
Extension Period. Diaries will be returned to 
the site and reviewed by the site personnel to 
ensure correct use/dosing of BRV. 
Sections 8.1.4 
and 8.2.4 
Extension Period Visit 2 will be 
performed when the subject enters 
the long-term study (see Section 
8.1.4.2). 
Extension Period Visit 2 will be 
performed on the same day when the 
subject enters the long-term study (see 
Section 8.1.4.2). 
Modified to clarify that EPV2 will not only be 
performed if a subject transitions to the Follow-
up study N01266 but on that particular day. 
Sections 
8.1.4.1, 
8.1.4.2, 
8.2.4.1 and 
8.2.4.2 
Not applicable 
Review of BRV dosing diary (only if 
oral BRV is administered at home) 
Introduction of a dosing diary to facilitate 
parents´ recording of BRV oral solution 
administered at home during the BRV 
Extension Period. Diaries will be returned to 
the site and reviewed by the site personnel to 
ensure correct use/dosing of BRV. 
Sections 
8.1.4.3 and 
8.2.4.3 
Not applicable 
Review of BRV dosing diary 
Introduction of a dosing diary to facilitate 
parents´ recording of BRV oral solution 
administered at home during the BRV 
Extension Period.. Diaries will be returned to 
the site and reviewed by the site personnel to 
ensure correct use/dosing of BRV. 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Sections 
8.1.4.4 and 
8.2.4.4 
Not applicable 
Discussion of BRV dosing diary 
Introduction of a dosing diary to facilitate 
parents´ recording of BRV oral solution 
administered at home during the BRV 
Extension Period. Diaries will be discussed 
over the phone to ensure correct use/dosing of 
BRV. 
Sections 
8.1.4.2 and 
8.2.4.2 
The EPV2 will be performed when 
the subject enters the long-term 
study. 
The EPV2 will be performed on the 
same day when the subject enters the 
long-term study. 
Modified to clarify that EPV2 will not only be 
performed if a subject transitions to the Follow-
up study N01266 but on that particular day. 
Section 8.2.5  
Video-EEG 
At least a 1-hour video-EEG on the 
final day of the Down-Titration Period 
(during the Down-Titration Period, 
additional video-EEGs can be 
performed at the investigator´s 
discretion) 
Description of the video-EEG that will be 
recorded at the end of the Down-Titration 
Period was specified to clearly separate this 
assessment from the 24-hour continuous video-
EEG performed during the Evaluation Period.  
Also, adding clarification that the protocol 
allows other video-EEGs to be performed in the 
Down-Titration Period at the discretion of the 
Investigator. 
Section 9.1 
Pharmacokinetic samples will be 
obtained either through an existing 
central line or taken from routinely 
performed heel-pricks. 
Pharmacokinetic samples will be 
obtained either through a venous or 
arterial catheter or taken from 
routinely performed heel-pricks. 
Description of the method of blood drawing for 
the PK analysis was specified based on 
feedback received from investigators. The 
former term “existing central line” was too 
specific to cover all the different possible routes 
of drawing blood from individual patients. 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 
11.1.1.3 
AST/ALT/ALP >3x ULN 
according to the subject’s GA and 
the site’s normal values for that GA 
AST, ALT or ALP values ≥3x ULN 
according to the subject’s GA and the 
site’s normal values for that GA, with 
the following exception: 
For subjects with perinatal asphyxia, if 
initial and peak LFT elevation occurs 
within 5 days after birth, and if the 
time course of the elevation of LFT is 
compatible with hepatic injury due to 
perinatal asphyxia (ie, peak LFT 
elevation within few days after birth, 
and subsequent normalization until up 
to day 14 after birth) only AST, ALT 
or ALP elevation ≥5x ULN must be 
reported as an AE of special interest. 
The description of AESI associated with PDILI 
was aligned with the PDILI criterion specified 
in section 6.3.1. 
Figure 11-1 
Not applicable 
Is the AE a PDILI event that leads to 
discontinuation? (see Section 11.2.1) 
Information added for consistency with the 
change made to section 11.1.1.3 (description of 
AESI associated with PDILI) 
Sections 
11.1.6 and 
13.8.3 
The DMC will consist of 3 voting 
members, none of whom will be 
involved in the conduct of the 
study, either by management or 
participation 
The DMC will consist of 4 voting 
members, none of whom will be 
involved in the conduct of the study, 
either by management or participation. 
The number of voting DMC members was 
increased to cover the medical expertise needed 
to assess PK and safety data for the evaluation 
of the risk-benefit profile in relation to the 
overall progress of the study. 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 
11.2.1.1 
Potential drug-induced liver injury 
events require notification of the 
Medical Monitor within 24 hours, 
and the subject must be discussed 
with the Medical Monitor as soon 
as possible. If applicable, the 
subject must also be discussed with 
the local hepatologist. The local 
hepatologist is the expert usually 
consulted by the treating physician 
for assessment and management of 
potential hepatic disease. This 
would usually be a hepatologist, but 
may be a gastroenterologist. If 
determined necessary, this 
discussion should be followed by a 
full hepatology assessment (see 
Section 11.2.1.3) and SAE report (if 
applicable). 
Potential drug-induced liver injury 
events require notification of the 
Medical Monitor within 24 hours, and 
the subject must be discussed with the 
Medical Monitor as soon as possible. 
If applicable, the subject may also be 
discussed with the local hepatologist. 
The local hepatologist is the expert 
usually consulted by the treating 
physician for assessment and 
management of potential hepatic 
disease. This would usually be a 
hepatologist, but may be a 
gastroenterologist or neonatologist 
with relevant expertise. If determined 
necessary, this discussion should be 
followed by a full assessment (see 
Section 11.2.1.3) and SAE report (if 
applicable). 
Modified based on feedback received from 
Investigators to better reflect the qualification 
of medical personnel needed and available on a 
local level to discuss cases of PDILI. 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 
11.2.1.3 
The measurements and additional 
information required for the 
assessment of PDILI events when 
there is a reasonable possibility that 
they may have been caused by the 
IMP are detailed in Table 11-3 
(laboratory measurements) and 
Table 11-4 (additional information). 
Results of the laboratory 
measurements and information 
collected are to be submitted to the 
Sponsor on the corresponding 
eCRF. If the medical history of the 
subject indicates a requirement for 
other assessments not included 
below, these additional assessments 
should be completed and submitted, 
as applicable. 
All blood samples will be tested 
locally. 
Table 11-3 shows the PDILI 
laboratory measurements to be 
assessed.  
The measurements and additional 
information recommended for the 
assessment of PDILI events when 
there is a reasonable possibility that 
they may have been caused by the IMP 
are detailed in Table 11-3 (laboratory 
measurements) and Table 11-4 
(additional information). Results of the 
laboratory measurements and 
information collected are to be 
submitted to the Sponsor on the 
corresponding eCRF. If the medical 
history of the subject indicates a 
requirement for other assessments not 
included below, these additional 
assessments should be completed and 
submitted, as applicable. 
All blood samples will be tested 
locally. 
Table 11-3 shows the PDILI laboratory 
measurements recommended to be 
assessed. 
Additional laboratory tests were included which 
cover causes of PDILI in neonates. In order to 
limit the extent of laboratory and other 
examinations to a minimum, these tests are 
considered as recommendations and leave it at 
the Investigator´s discretion to decide which 
tests/measurements are appropriate within the 
given situation, taking into consideration the 
clinical status and medical history of subjects 
and their mothers. 
Section 11.3.6 Video-EEG monitoring will be 
assessed for the subject’s reactivity, 
in addition to the interpretation of 
the N-PASS in terms of sedation 
status. 
Video-EEG monitoring performed 
during the Evaluation Period will be 
assessed for the subject’s reactivity, in 
addition to the interpretation of the N-
PASS in terms of sedation status. 
Description of the video-EEG assessed for the 
subject´s reactivity was specified to clearly 
separate it from the 1-hour video-EEG recorded 
on the final day of the Down-Titration Period. 
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In addition, the following intext tables were modified: 
Table 11-2: Required investigations and follow-up for PDILI 
Laboratory value 
Immediate 
Follow-Up 
ALT/ AST/ALP 
Conjugated 
bilirubina 
 
Consultation requirements 
Actions 
Testing 
Evaluation 
≥3xULN 
according to the 
subject’s GA and 
site’s normal value 
NA 
Hepatology consultation. 
Medical Monitor must be 
notified within 24 hours (eg, 
laboratory alert) and subject 
discussed with Medical 
Monitor ASAPb 
Immediate, 
permanent IMP 
discontinuation. 
Essential: Must have repeat liver 
chemistry values and additional 
testing completed ASAP (see 
Section 11.2.1.1); recommended 
to occur at the site with HCP. 
Monitoring of liver 
chemistry values at least 
twice per week until values 
normalize, stabilize, or 
return to within Baseline 
values. 
≥2x and ≤3xULN 
according to the 
subject’s GA and 
site’s normal value 
≥2mg/dL 
NA 
≥2mg/dL 
ASAP=as soon as possible; GA=gestational age; HCP=healthcare practitioner; IMP=investigational medicinal product; NA=not applicable; PDILI=potential 
drug-induced liver injury; ULN=upper limit of normal 
a Any requirement for phototherapy or exchange transfusion due to elevated bilirubin necessitates withdrawal regardless of laboratory values.  
b Details provided in Section 11.2.1.1. The local hepatologist is the expert usually consulted by the treating physician for assessment and management of 
potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist. 
To align the investigations and follow-up for PDILI with the updated exclusion criterion #7, withdrawal criterion #6 and PDILI 
criterion, Table 11-2 was changed to: 
 
 
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Table 11-2: Required investigations and follow-up for PDILI 
Patient 
population 
Laboratory value 
Immediate 
Follow-Up 
 
ALT/ 
AST/ALP 
Conjugated 
bilirubina 
Consultation 
requirements 
Actions 
Testing 
Evaluation 
Subjects 
without 
perinatal 
asphyxia 
≥3xULN 
according to 
the subject’s 
GA and site’s 
normal value 
NA 
Hepatology 
consultation (see 
Section 11.2.1). 
Medical Monitor 
must be notified 
within 24 hours (eg, 
laboratory alert) and 
subject discussed 
with Medical 
Monitor ASAPb 
Immediate, permanent 
IMP discontinuation. 
Essential: Must have repeat 
liver chemistry values and 
additional testing 
completed ASAP (see 
Section 11.2.1.1); 
recommended to occur at 
the site with HCP. 
Monitoring of liver 
chemistry values at least 
twice per week until 
values normalize, 
stabilize, or return to 
within Baseline values. 
Subjects with 
perinatal 
asphyxiac 
≥5xULN 
according to 
the subject’s 
GA and site’s 
normal value 
NA 
All subjects 
NA 
≥2mg/dL 
ASAP=as soon as possible; GA=gestational age; HCP=healthcare practitioner; IMP=investigational medicinal product; NA=not applicable; PDILI=potential 
drug-induced liver injury; ULN=upper limit of normal 
a Any requirement for phototherapy or exchange transfusion due to elevated bilirubin necessitates withdrawal regardless of laboratory values. 
b Details provided in Section 11.2.1.1. The local hepatologist is the expert usually consulted by the treating physician for assessment and management of 
potential hepatic disease. This would usually be a hepatologist, but may be a gastroenterologist. 
c For subjects with perinatal asphyxia, if initial and peak LFT elevation occurs within 5 days after birth, and if the time course of LFT elevation is compatible 
with  hepatic injury due to perinatal asphyxia (ie, peak LFT elevation within few days after birth, and subsequent normalization until up to day 14 after 
birth): in case  AST, ALT or ALP elevation ≥5x ULN occurs within 5 days after birth in patients with perinatal asphyxia and suspected hepatic hypoxic 
injury, study drug must  be discontinued and LFTs retested within 24 hours. If AST, ALT and ALP values confirmed <5x ULN, the subject may restart 
study medication after  consultation with and approval by the Medical Monitor 
 
 
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Table 11-3: PDILI laboratory measurements 
Virology-related 
(virology tests dependent on local 
vaccination schedule) 
Hepatitis A IgM antibody 
Hepatitis E IgM antibody 
Hepatitis C IgM 
HBsAg 
Cytomegalovirus testing (culture or polymerase chain reaction) of saliva/urine 
Epstein-Barr viral capsid antigen IgM antibody  
Hematology 
Eosinophil count 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
Serum CPK and LDH to evaluate possible muscle injury causing transaminase elevation 
Additional 
Prothrombin time/INR 
CPK=creatine phosphokinase; HBsAg=hepatitis B virus surface antigen; IgM=immunoglobulin M; INR=international normalized ratio; LDH=lactate 
dehydrogenase; PDILI=potential drug-induced liver injury 
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To include additional laboratory tests which cover causes of PDILI in neonates and to limit the extent of laboratory and other 
examinations to a minimum, these tests are considered as recommendations and leave it at the Investigator´s discretion to decide 
which tests/measurements are appropriate within the given situation, taking into consideration the clinical status and medical history 
of the subject and its mother, Table 11-3 was changed to: 
Table 11-3: Recommended PDILI laboratory measurementsa 
Virology-related 
(virology tests dependent on local 
vaccination schedule) 
HSV blood PCR (or other testing: HSV IgM, viral culture of blood or CSF, CSF PCR) 
Enterovirus blood PCR (or other testing) 
Hepatitis A IgM antibodyb 
Hepatitis E IgM antibodyb 
Hepatitis C IgMb 
HBsAgb 
Cytomegalovirus testing (culture or polymerase chain reaction) of saliva/urine 
Epstein-Barr viral capsid antigen IgM antibody  
Hematology 
Eosinophil count 
Urinalysis 
Toxicology screen 
Chemistry 
Amylase 
Serum CPK and LDH to evaluate possible muscle injury causing transaminase elevation 
Lactate, pyruvate (mitochondrial screen) 
Plasma acylcarnitine profile (fatty acid oxidation defects) 
Ferritin (screen for gestational alloimmune liver disease [neonatal hemochromatosis]) 
Confirm newborn screening results (galactosemia and tyrosinemia) 
Serum amino acid profile (urea cycle and metabolic) 
Additional 
Prothrombin time/INR 
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Table 11-3: Recommended PDILI laboratory measurementsa 
CPK=creatine phosphokinase; CSF=cerebrospinal fluid; HBsAg=hepatitis B virus surface antigen; HSV=herpes simplex virus; IgM=immunoglobulin M; 
INR=international normalized ratio; LDH=lactate dehydrogenase; PCR=polymerase chain reaction; PDILI=potential drug-induced liver injury 
a Recommended testing is at the discretion of the Investigator and should be individualized appropriately based on clinical situation 
b Maternal viral hepatitis status may be considered 
 
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Table 11-4: PDILI information to be collected 
New or updated information 
Concomitant medications prescription with dosages and dates should be included. 
Pertinent medical history, including the following: 
• 
Adverse reactions to drugs 
• 
Allergies 
• 
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin deficiency) 
The appearance or worsening of clinical symptoms of hepatitis or hypersensitivity  
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function 
Results of liver imaging or liver biopsy, if done 
Results of any specialist or hepatology consult, if done 
Any postmortem/pathology reports 
PDILI=potential drug-induced liver injury 
 
For the evaluation of potential cardiac dysfunction in case of PDILI, Table 11-4 was changed to 
 
 
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Table 11-4: PDILI information to be collected 
New or updated information 
Concomitant medications prescription with dosages and dates should be included. 
Pertinent medical history, including the following: 
• 
Adverse reactions to drugs 
• 
Allergies 
• 
Relevant family history or inheritable disorders (eg, Gilbert’s syndrome, alpha-1 antitrypsin deficiency) 
The appearance or worsening of clinical symptoms of hepatitis or hypersensitivity  
Recent clinically significant hypotension or hypoxemia with compromised cardiopulmonary function 
Results of liver imaging or liver biopsy, if done 
Results of any specialist or hepatology consult, if done 
Results of Echocardiogram (for evaluation of potential cardiac dysfunction) and abdominal ultrasound with 
Doppler (vascular and anatomic), if done 
Any postmortem/pathology reports 
PDILI=potential drug-induced liver injury 
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17.2 
Protocol Amendment 2 
Rationale for the amendment 
The primary purpose of this non-substantial amendment is to adapt the definition of the subjects´ 
age at enrollment based on a request from the European Medicines Agency´s (EMA) Paediatric 
Committee (PDCO). In addition, editorial changes were made to clarify different aspects of the 
study design. Administrative and stylistic changes may not be included in the summary table of 
specific changes since they are considered minor. 
Modifications and changes 
Global changes 
• The definition of the subjects´ age at enrollment was adapted to a request from PDCO 
• MDZ treatment in the Exploratory Cohort during the 3-hour interval prior to start of BRV 
treatment was clarified 
• Timepoints for the dispense of BRV for subjects entering the BRV Extension Period were 
added 
• Timepoints for the collection of PK samples were specified 
• Number of DMC voting members was decreased from 4 to 3 members 
• Sections referring to Monitoring and Source Data were aligned with the updated UCB 
protocol template 
• Sections referring to the treatment with Permitted/Prohibited Concomitant Medication and 
Rescue Medication were edited for clarification 
 
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Specific changes 
Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Sections 
1, 2.3, 5.4.1, 
6.1 
Subject is male or female, with an 
age at birth of at least 34 weeks of 
GA and up to 28 days of postnatal 
age at the time of enrollment. 
Subject is male or female, with an age 
at birth of 34 weeks to less than 42 
weeks of GA and up to 28 days of 
postnatal age at the time of 
enrollment. 
The definition of the subject age at enrollment 
was adapted based on a request from PDCO. 
Sections 
1, 5.1, 7.2 
For the Exploratory Cohort (first 
step), enrolled subjects will receive a 
therapeutic dose of MDZ (dose of 
MDZ is at the discretion of the 
Investigator) prior to receiving BRV. 
For the Exploratory Cohort (first 
step), enrolled subjects will receive 
one or multiple therapeutic doses of 
MDZ (dose of MDZ is at the 
discretion of the Investigator) prior to 
receiving BRV. 
Edited to clarify that MDZ treatment in the 
Exploratory Cohort during the 3 hours prior to 
the start of BRV treatment is not limited to a 
single MDZ dose. 
Section 5.1.1 
Evaluation Period (in total, 51 hours: 
3 hours for the evaluation of MDZ 
and 48 hours for the evaluation of 
BRV): Subjects will receive iv MDZ 
at a therapeutic dose (MDZ dose is at 
the discretion of the Investigator). 
Evaluation Period (in total, 51 hours: 
3 hours for the evaluation of MDZ 
and 48 hours for the evaluation of 
BRV): Subjects will receive iv MDZ 
(one or multiple therapeutic doses; 
MDZ dose is at the discretion of the 
Investigator). 
Aligned with the change described above. 
Section 4.2.1 
The use of rescue medication will 
affect the analysis of the key efficacy 
variables in the different study 
Cohorts (see Section 7.8.3). 
The use of rescue medication will 
affect the analysis of the key efficacy 
variables in the different study 
Cohorts (see Section 13.5.1). 
Reference to section 7.8.3 adjusted to the shift 
of text. 
Table 5-1 
Not applicable 
Dispense BRV for the BRV 
Extension Periodk 
Row added to indicate BRV dispense at the end 
of the Evaluation Period (after 48 hours).  
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Table 5-1 
Not applicable 
k Dispensing of BRV is only 
 applicable if the subject enters the 
 BRV Extension Period 
Footnote k added to further explain the addition 
of BRV dispensing at the end of the Evaluation 
Period. 
Table 5-2 
Not applicable 
Dispense BRV for the BRV 
Extension Periodm 
Row added to indicate BRV is dispensed at the 
end of the Evaluation Period (after 96 hours). 
Table 5-2 
Not applicable 
m Dispensing of BRV is only 
 applicable if the subject enters the 
 BRV Extension Period 
Footnote m added to further explain the 
addition of BRV dispensing at the end of the 
Evaluation Period. 
Table 5-2 
b If subjects do not benefit from 
BRV treatment after 96 hours of 
BRV administration, BRV 
administration will be stopped and 
replaced by another AED; 
however, the subject’s participation 
in the Evaluation Period will 
continue. 
b If subjects do not benefit from BRV 
 treatment after 96 hours of BRV 
 administration, BRV administration 
 will be stopped and replaced by 
 another AED; however, the 
 subject’s participation in the study 
 will continue. 
In the Confirmatory Cohort all subjects will 
complete the Evaluation Period after 96 hours. 
Subjects who do not benefit from BRV at this 
point will enter the Down-Titration and Safety 
Follow-up Period. The subject´s participation in 
the “study” will hence continue. 
Table 5-3 
g If the subject enters the long-term 
 study, no medication from 
 N01349 will be dispensed in 
 EPV2. If the subject does not 
 enter the long-term study, BRV 
 from N01349 will be administered 
 for down-titration 
g If the subject enters the long-term 
study, no study drug from N01349 
will be dispensed in EPV2. If the 
subject does not enter the long-term 
study, BRV from N01349 will be 
administered for down-titration 
(only applicable to subjects from the 
Confirmatory Cohorts). 
Footnote g aligned with modifications to 
sections 8.1.4.2 and 8.2.4.2. 
Figure 5-4 
a Switching to another AED or 
 addition of rescue medication is 
a Switching to another AED or 
addition of rescue medication 
Footnote a aligned with modifications to 
section 7.8.3. 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
 only permitted 3 hours after the 
 first BRV administration. 
should only occur following 3 hours 
after the first BRV administration. 
 
Section 7.8.1 
Prior to BRV administration, the 
following AEDs are permitted 
during the study: 
• 
PB 
• 
MDZ (Exploratory Cohort only) 
For the Exploratory Cohort, subjects 
will be permitted to receive any 
concomitant medications at any time 
during the study after BRV 
administration as deemed necessary 
by the Investigator. 
For the Confirmatory Cohorts, 
subjects will be permitted to receive 
AEDs only 3 hours following the 
first BRV administration. Other 
concomitant medications will be 
permitted as deemed necessary by 
the Investigator. 
Concomitant treatment with non-
AEDs is permitted for the Exploratory 
and Confirmatory Cohort(s) at any 
time throughout the study.  
Concomitant treatment with AEDs is 
permitted as follows: 
Prior to first BRV administration: 
• 
PB 
• 
MDZ (Exploratory Cohort only) 
After first BRV administration: 
• 
Any AEDs (including MDZ) 
− 
Exploratory Cohort: from 
first BRV administration  
− 
Confirmatory Cohorts: from 3 
hours following first BRV 
administration 
Simplified to clarify 1) the concomitant 
treatment with non-AEDs and AEDs and 2) the 
treatment of concomitant AEDs relative to the 
first administration of BRV. 
Section 7.8.2 
For the Confirmatory Cohorts only, 
subjects will not be permitted to 
receive treatments for neonatal 
seizures (other than the specified PB 
doses) prior to and for the first 3 
For the Exploratory Cohort, subjects 
will not be permitted to receive 
treatments for neonatal seizures (other 
than the specified PB doses and 
MDZ) prior to the first BRV 
administration. 
Description of prohibited concomitant 
treatment in the Exploratory Cohort added for 
clarification. 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
hours after the first BRV 
administration. 
For the Confirmatory Cohorts, 
subjects will not be permitted to 
receive treatments for neonatal 
seizures (other than the specified PB 
doses) prior to and for the first 3 
hours after the first BRV 
administration. 
Section 7.8.3 
Rescue medication can be given at 
any time if considered necessary by 
the Investigator.  
However, it is prohibited for 
subjects to receive rescue medication 
prior to BRV dosing for the 
Exploratory Cohort (except for MDZ 
as scheduled in the Protocol) and 
during the 3 hours after the initial 
dose of BRV for the Confirmatory 
Cohorts. If this occurs, subjects will 
be considered BRV nonresponders. 
For the Confirmatory Cohorts this 
means: 
• 
For the analysis of the main 
efficacy variable, subjects must 
not have used any rescue 
medication (including BZDs) 
during the first 3 hours after 
initiation of BRV treatment to be 
considered BRV responders.  
Rescue medication in this study is 
considered as any treatment with 
AEDs. Rescue medication can be 
given at any time if considered 
necessary by the Investigator.  
However, during the Evaluation 
Period rescue medication should not 
be administered – if possible – in the 
following time frames: 
• 
Prior to BRV dosing for the 
Exploratory Cohort (except for 
MDZ as scheduled in the 
Protocol). 
• 
During the first 3 hours after the 
initial dose of BRV for the 
Confirmatory Cohorts. If this 
occurs, subjects will be 
considered BRV nonresponders. 
Edited for clarification. Text about the analysis 
of the main efficacy variable and key efficacy 
variables was moved to section 13.5.1 
(Analysis of the key efficacy variables). 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
• 
For the analysis of the key 
efficacy variables (other than the 
main efficacy variable) and other 
efficacy variables, subjects must 
not have used >1 dose of rescue 
medication following the first 3 
hours after initiation of BRV 
treatment to be considered BRV 
responders. A single dose of 
short-acting BZD as rescue 
medication is allowed, but only 
after 3 hours subsequent to the 
initiation of treatment with BRV. 
Sections 
8.1.4 and 
8.2.4 
Not applicable 
For subjects entering the BRV 
Extension Period, study drug will be 
dispensed at the end of the Evaluation 
Period. 
Added in conjunction with above described 
changes to Tables 5-1 and 5-2. 
Sections 
8.1.4.2 and 
8.2.4.2 
• 
BRV administration/dispense (If 
the subject enters the long-term 
study, no medication from 
N01349 will be dispensed in 
EPV2. If the subject does not 
enter the long-term study, BRV 
from N01349 will be 
administered for down-titration).  
• 
BRV administration/dispense. If 
the subject enters the long-term 
study, no study drug from 
N01349 will be dispensed at 
EPV2. If the subject does not 
enter the long-term study, BRV 
from N01349 will be 
administered for down-titration 
(only applicable to subjects from 
the Confirmatory Cohorts). 
Edited for clarification.  
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 9.1 
For the determination of plasma 
concentrations of BRV, BRV 
metabolites, and plasma 
concentrations of concomitant AEDs 
(PB and PHT), up to 6 blood 
microsamples (65μL/sample) will be 
collected per subject in the 
Exploratory (3 to 6 blood 
microsamples) and Confirmatory 
Cohorts (up to 6 blood 
microsamples) at 3 predetermined 
timepoints per day.  
Pharmacokinetic samples will be 
obtained either through a venous or 
arterial catheter or taken from 
routinely performed heel-pricks. 
Blood for PK samples should be 
drawn from a line different to that of 
the BRV infusion. Three PK samples 
of blood will be collected at the 
following predetermined timepoints 
at the first day of the Evaluation 
Period: 30 to 60 minutes, 2 to 
4 hours, and 8 to 12 hours after the 
start of the most recent BRV 
infusion. For the Exploratory Cohort 
the same timepoints apply to the 
second day of the 48-hour 
Evaluation Period. For the 
Confirmatory Cohort(s), the second 
For the determination of plasma 
concentrations of BRV and BRV 
metabolites, up to 6 blood 
microsamples (65μL/sample) will be 
collected per subject in the 
Exploratory (3 to 6 blood 
microsamples) and Confirmatory 
Cohorts (up to 6 blood microsamples) 
at 3 predetermined timepoints per 
day. An additional microsample 
(65μL) will be collected per subject 
for the determination of plasma 
concentrations of concomitant AEDs 
(PB and PHT). 
Pharmacokinetic samples will be 
obtained either through a venous or 
arterial catheter or taken from 
routinely performed heel-pricks. 
Blood for PK samples should be 
drawn from a line different to that of 
the BRV infusion. Three BRV PK 
samples of blood will be collected at 
the following predetermined 
timepoints at the first day of the 
Evaluation Period: 30 to 60 minutes, 
2 to 4 hours, and 8 to 12 hours after 
the start of the most recent BRV 
infusion. For the Exploratory Cohort 
the same timepoints apply to the 
second day of the 48-hour Evaluation 
Edited for clarification. 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
set of 3 PK samples will be collected 
at the same timepoints on 1 of the 
other days of the 96-hour Evaluation 
Period. It will be acceptable if these 
samples are drawn on different days. 
The timepoints for the collection of 
PK samples are described in 
Table 5‒4 for the Exploratory Cohort 
and in Table 5‒5 for the 
Confirmatory Cohorts. An additional 
microsample (65μL) will be 
collected for the determination of 
plasma concentrations of 
concomitant AEDs (PB and PHT). 
The AED PK sample should be 
collected 3 hours after the start of the 
initial BRV administration. 
Period. For the Confirmatory 
Cohort(s), the second set of 3 BRV 
PK samples will be collected at the 
same timepoints on 1 of the other 
days of the 96-hour Evaluation 
Period. It will be acceptable if these 
samples are drawn on different days. 
The AED PK sample should be 
collected 3 hours after the start of the 
initial BRV administration. The 
timepoints for the collection of PK 
samples are described in Table 5‒4 
for the Exploratory Cohort and in 
Table 5‒5 for the Confirmatory 
Cohorts. 
Section 
11.1.1.2.1 
In addition, the following are 
expected SAEs in babies with HIE: 
In addition, the following are 
anticipated SAEs in babies with HIE: 
The term describing SAEs was clarified since 
SAEs listed are anticipated to occur in babies 
with HIE independent of exposure to BRV. 
Sections 
11.1.6 and 
13.8.3 
The DMC will consist of 4 voting 
members, none of whom will be 
involved in the conduct of the study, 
either by management or 
participation.  
The DMC will consist of 3 voting 
members, none of whom will be 
involved in the conduct of the study, 
either by management or 
participation. 
The Biostatistician initially counted as 1 of the 
4 voting DMC members will be supporting the 
DMC as a subject matter expert but not act as 
voting DMC member. Hence, the number of 
voting DMC members was corrected. Since the 
3 voting DMC members are health 
professionals, the medical expertise covered by 
the DMC remains unchanged. 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 12.2 
UCB (or designee) will monitor the 
study to meet the Sponsor’s 
monitoring 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 
contract research organization 
(CRO) or a contract monitor. 
Monitoring of the study will be 
delegated by UCB to a CRO. The 
CRO will monitor the study to meet 
the CRO’s monitoring Standard 
Operating Procedures (SOPs), 
ICH-GCP guideline, and applicable 
regulatory requirements, and to 
ensure that study initiation, conduct, 
and closure are adequate. 
Aligned with the updated UCB protocol 
template. 
Section 12.2.1 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 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 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 or 
other printouts, completed scales, 
quality of life questionnaires, or 
video, for example. Source 
documents should be kept in a secure, 
limited access area. 
Aligned with the updated UCB protocol 
template. 
Section 13.5.1 Not applicable 
For the Confirmatory Cohorts this 
means: 
• 
For the analysis of the main 
efficacy variable, subjects must 
not have used any rescue 
medication (including BZDs) 
Moved from section 7.8.3. 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
during the first 3 hours after 
initiation of BRV treatment to be 
considered BRV responders.  
• 
For the analysis of the key 
efficacy variables (other than the 
main efficacy variable) and other 
efficacy variables, subjects must 
not have used >1 dose of rescue 
medication following the first 3 
hours after initiation of BRV 
treatment to be considered BRV 
responders. A single dose of 
short-acting BZD as rescue 
medication is allowed, but only 
after 3 hours subsequent to the 
initiation of treatment with BRV. 
Figure 11-1 
Does the AE meet any of the 
following?  
• 
Potentially related to BRV 
(see Section 11.1.1.2.1) 
Does the AE meet any of the 
following?  
• 
Potentially related to BRV 
Reference deleted since AEs described in 
section 11.1.1.2.1 are observed in babies and in 
babies with HIE regardless of study drug 
exposure. 
 
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Table 5-4: 
Schedule for PK Sampling (Exploratory Cohort)Table  
Assessment 
MDZ 
48-hour Evaluation Period 
Time relative to the start of the latest BRV infusion given per day 
Day 1a 
Day 2ab 
30-60minc 
2-4h 
8-12h 
30-60min 
2-4h 
8-12h 
BRV PK samplesd  
X 
X 
X 
X 
X 
X 
AED PK sample 
 
 
Xe 
 
 
 
 
AED=antiepileptic drug; BRV=brivaracetam; h=hours; MDZ=midazolam; min=minutes; PK=pharmacokinetic(s) 
Note: Blood for PK samples should be drawn from a line different to that of the BRV infusion. 
a Blood sample collection 8-12 hours is relative to BRV dosing only if BRV is administered once per day. In case of 
a second BRV dose on the same day, the third blood sample should be collected 30 to 60 minutes after the start of 
the second BRV infusion. 
b Blood sampling is only needed on Day 2 if subjects are dosed with BRV on Day 2. 
c The PK sample should be collected 30 to 60 minutes after the start of the BRV infusion.  
d The PK sampling timepoints for the first 3 samples of the Exploratory Cohorts are as follows: 30 to 60 minutes, 
2 to 4 hours, and 8 to 12 hours after the start of the most recent BRV infusion. The second set of 3 samples will be 
collected at the same timepoints on the second day of the 48-hour Evaluation Period. 
e The AED PK sample should be collected 3 hours after the start of the initial BRV administration. 
 
For clarification of timepoints at which PK blood samples will be collected in the Exploratory 
Cohort, Table 5-4 was changed to 
Table 5-4: 
Schedule for PK Sampling (Exploratory Cohort)  
Assessment 
 
48-hour Evaluation Period 
Time relative to the start of the most recent BRV infusion  
Day 1 
Day 2a 
30-60minb 
2-4h 
8-12h 
30-60min 
2-4h 
8-12h 
BRV PK samplesc 
X 
X 
X 
X 
X 
X 
AED PK sample 
 
Xd 
 
 
 
 
AED=antiepileptic drug; BRV=brivaracetam; h=hours; MDZ=midazolam; min=minutes; PK=pharmacokinetic(s) 
Note: Blood for PK samples should be drawn from a line different to that of the BRV infusion. 
a Blood sampling is only needed on Day 2 if subjects are dosed with BRV on Day 2. 
b The first PK sample should be collected 30 to 60 minutes after the start of the BRV infusion.  
c The BRV PK sampling timepoints for the first 3 samples of the Exploratory Cohorts are as follows: 30 to 
60 minutes, 2 to 4 hours, and 8 to 12 hours after the start of the most recent BRV infusion. The second set of 
3 samples will be collected at the same timepoints on the second day of the 48-hour Evaluation Period. 
d The AED PK sample should be collected 3 hours after the start of the initial BRV administration. 
 
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Table 5-5: 
Schedule for PK Sampling (Confirmatory Cohorts) 
Assessment 
96-hour Evaluation Period 
Time relative to the start of the latest BRV infusion given per day 
 
Day 1a 
Day 2a 
Day 3a 
Day 4a 
30-60mi
nc 
2-4
h 
8-12
h 
30-60m
in 
2-4
h 
8-12
h 
30-60m
in 
2-4
h 
8-12
h 
30-60m
in 
2-4
h 
8-12
h 
BRV PK samp
lesb 
X 
X 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
AED PK 
sample 
 
Xd 
 
 
 
 
 
 
 
 
 
 
AED=antiepileptic drug; BRV=brivaracetam; h=hours; PK=pharmacokinetic(s); min=minutes; (X)=optional for 
that day 
Note: Blood for PK samples should be drawn from a line different to that of the BRV infusion.  
a  Blood sample collection 8-12 hours is relative to BRV dosing only if BRV is administered once per day. In case 
of a second BRV dose on the same day, the third blood sample should be collected 30 to 60 minutes after the 
start of the second BRV infusion.  
b The PK sampling timepoints for the first 3 samples of the Confirmatory Cohorts are as follows: 30 to 
60 minutes, 2 to 4 hours, and 8 to 12 hours after the start of the most recent BRV infusion. The second set of 
3 PK samples will be collected within the same timeframes as the first set on one of the following days: either 
Day 2 (post-24 hours), OR Day 3 (post-48 hours) OR Day 4 (post-72hours). It is acceptable if these samples are 
drawn on different days. 
c The first PK sample will be collected 30 to 60 minutes after the start of the BRV infusion. 
d The AED PK sample should be collected 3 hours after the start of the initial BRV administration. 
 
For clarification of timepoints at which PK blood samples should be collected in the 
Confirmatory Cohorts, Table 5-5 was changed to 
 
 
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Table 5-5: 
Schedule for PK Sampling (Confirmatory Cohorts) 
Assessment 
96-hour Evaluation Period 
Time relative to the start of the most recent BRV infusion 
 
Day 1 
Day 2 
Day 3 
Day 4 
30-60mi
na 
2-4
h 
8-12
h 
30-60m
in 
2-4
h 
8-12
h 
30-60m
in 
2-4
h 
8-12
h 
30-60m
in 
2-4
h 
8-12
h 
BRV PK samp
lesb 
X 
X 
X 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
(X) 
AED PK 
sample 
 
Xc 
 
 
 
 
 
 
 
 
 
 
AED=antiepileptic drug; BRV=brivaracetam; h=hours; PK=pharmacokinetic(s); min=minutes; (X)=optional for 
that day 
Note: Blood for PK samples should be drawn from a line different to that of the BRV infusion.  
a The first PK sample will be collected 30 to 60 minutes after the start of the BRV infusion. 
b The BRV PK sampling timepoints for the first 3 samples of the Confirmatory Cohorts are as follows: 30 to 
60 minutes, 2 to 4 hours, and 8 to 12 hours after the start of the most recent BRV infusion. The second set of 
3 PK samples will be collected within the same timeframes as the first set on one of the following days: either 
Day 2 (post-24 hours), OR Day 3 (post-48 hours) OR Day 4 (post-72hours). It is acceptable if these samples are 
drawn on different days. 
c The AED PK sample should be collected 3 hours after the start of the initial BRV administration. 
 
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17.3 
Protocol Amendment 3 
Rationale for the amendment 
The primary purpose of this non-substantial amendment is to incorporate feedback and 
clarification based on IEC and Investigator requests. Administrative and stylistic changes may 
not be included in the summary table of specific changes since they are considered minor. 
Modifications and changes 
Global changes 
• Modification of safety lab panel 
• Alignment of language presented in the Pediatric Investigation Plan 
• Safety labs from third parties considered as medical history 
• Clarification of timepoints for weight measurements 
• Alignment of ALP measurement 
• Definition of BRV nonresponders 
• Use of VEEG traces recorded before parents consented for the determination of the Baseline 
VEEG 
• Continuous VEEG to be allowed interruption 
• PB treatment permitted to start prior to the subject’s admission into the study site, as well as 
allowed to be administered in 3 separate doses  
• Recommendations for subjects discontinuing BRV treatment 
• Blood sampling guidance 
• Adverse event recording clarification 
• Allowance of telephone consenting process 
• Clarification about the transition from N01349 to follow-up study N01266 
• Change in serious adverse event contact information  
• Dosing and data modeling clarification  
 
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Specific changes 
Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
STUDY 
CONTACT 
INFORMAT-
ION 
, 
 
8010 Arco Corporate Drive, 
 
 
Raleigh, NC 27617 
 
 
 
UCB BioSciences, Inc. 
8010 Arco Corporate Drive, 
 
Raleigh, NC 27617 
 
 
The clinical trial biostatistician has changed.  
STUDY 
CONTACT 
INFORMA-
TION 
  
Neonatal Neurologist 
 
Pediatric Neonatologist 
A member of the DMC has changed.  
SERIOUS 
ADVERSE 
EVENT 
REPORTING 
Europe: +32 2 386 24 21 
DS_ICT@ucb.com 
Europe: +32 238 66561 
PSRapidalert@ucb.com 
Change in serious adverse event contact 
information.  
Section 1 
As the patient population of neonates 
with electroencephalographic 
neonatal seizures (ENS) is limited, 
N01349 is designed with a 2-step 
approach to allow for confirmation 
(or adjustment) of dosing based on 
results from the first step 
(Exploratory Cohort) and evaluation 
of BRV efficacy in the second step 
(Confirmatory Cohorts). 
As the patient population of neonates 
with electroencephalographic 
neonatal seizures (ENS) is limited, 
N01349 is designed with a 2-step 
approach to allow for confirmation 
(or adjustment) of BRV dosing based 
on results from the first step 
(Exploratory Cohort) and evaluation 
of BRV efficacy in the second step 
(Confirmatory Cohorts). 
Specification of drug dosing.  
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 1 
Subjects will first receive 1 or 2 
doses of phenobarbital (PB) (total 
therapeutic administered dose of 20 
to 40mg/kg; dosing regimen at the 
Investigator’s discretion). 
Subjects will first receive 1 to 3 doses 
of phenobarbital (PB) (total 
therapeutic administered dose of 20 to 
40mg/kg; dosing regimen at the 
Investigator’s discretion). 
Based on Investigator feedback, the total PB 
dose of 20 to 40mg/kg may be administered 
over 3 separate doses.  
Section 1 
For the Exploratory Cohort (first 
step), enrolled subjects will receive 
one or multiple doses of a 
therapeutic dose of midazolam 
(MDZ) (dose of MDZ is at the 
discretion of the Investigator) prior 
to receiving BRV. 
For the Exploratory Cohort (first 
step), enrolled subjects will receive 
one or multiple doses or continuous 
infusion of a therapeutic dose of 
midazolam (MDZ) (dose and dosing 
frequency of MDZ are at the 
discretion of the Investigator) prior to 
receiving BRV. 
Dose frequency and continuous infusion are 
also at the discretion of the Investigator.  
Section 1 
This treatment represents the first 
use of BRV in neonates (0.5mg/kg 
bid), which is 4-fold less than the 
highest dosage of 4mg/kg/day that 
has been used previously in study 
N01263 (subjects ≥1 month old to 
<16 years of age; Section 2.2). 
This treatment represents the first use 
of BRV in neonates (0.5mg/kg bid), 
which is 4-fold less than the highest 
dosage of 4mg/kg/day that has been 
used previously in study N01263 
(Section 2.2). 
In BRV PK modeling studies CL0187 
and N01331, PK profiles were 
extrapolated allometrically to the 
neonatal age group from the pediatric 
data collected in N01263 (age range 
of ≥1 month to <16 years). A total of 
600 samples from 96 subjects were 
used for this modeling. The results of 
this modeling suggest that a dosing 
Age specification not needed.  
Data modeling details added.  
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
regimen of 2mg/kg bid in pediatric 
subjects ≥1 month to <16 years of age 
with a maximum of 100mg bid would 
result in plasma concentration profiles 
similar to those attained in older 
children and adults who received 
therapeutic doses of BRV (up to 
100mg bid). Since extrapolation of 
data from subjects ≥1 month to 
subjects ≤2 weeks may be imprecise 
due to variability in ontogeny in the 
metabolic and excretory functions in 
neonates, actual PK measurements 
conducted in the Exploratory Cohort 
of N01349 will be used to confirm the 
relationship between dose and plasma 
concentration in neonates. 
Section 1 
The iv dose and dosing frequency of 
BRV selected for the Confirmatory 
Cohorts will be determined by the 
evaluation of BRV plasma 
concentrations from the Exploratory 
Cohort to be within the range of 
plasma concentrations observed in 
children ≥1 month old who received 
BRV 4mg/kg/day. 
The iv dose and dosing frequency of 
BRV selected for the Confirmatory 
Cohorts will be determined by the 
evaluation of BRV plasma 
concentrations from the Exploratory 
Cohort, as well as by the PK 
modeling of N01263 data described 
above, to be within the range of 
plasma concentrations observed in 
children ≥1 month old who received 
BRV 4mg/kg/day. 
Per agency recommendation, clarification that 
BRV dose and dosing frequency is also 
determined by previous PK modeling of 
N01263 data.  
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Sections 1, 
5.1, 5.4.2 
Not applicable 
The recommendation to confirm or 
adjust the originally calculated BRV 
dose of the Confirmatory Cohorts of 
study N01349 will be given by the 
DMC after review of PK and safety 
data of the Exploratory Cohort.  
Clarification of DMC participation in 
determination of Confirmatory Cohort dosage.  
Sections 1, 
4.2.1, 10.1, 
13.5.1 
Not applicable 
Timespans of 30 minutes refer to the 
following intervals within the 2-hour 
period: 0 to ≤30 minutes, >30 to ≤60 
minutes, >60 to ≤90 minutes, and >90 
to ≤120 minutes. 
Clarification of 30-minute time intervals.  
Section 4.2.1 
• 
Absolute reduction and 
proportion of clinical seizures 
correlated with continuous 
VEEG from Baseline to the end 
of the 96-hour Evaluation 
Period, and each of the 3-hour 
intervals 
• 
Absolute and percent difference 
in clinical seizures at the end of 
the 24-hour Evaluation Period 
from Baseline for neonates with 
motor seizures at the time of 
inclusion 
 
Alignment of language presented in the 
Pediatric Investigation Plan.  
Section 4.3 
• 
Mechanical ventilation: 
− 
Number and percentage of 
subjects requiring ventilation 
during treatment with BRV 
over the Evaluation Period 
− 
Number and percentage of 
subjects requiring ventilation 
during treatment with other 
• 
Mechanical ventilation: 
− 
Number and percentage of 
subjects requiring mechanical 
ventilation during the 
Evaluation Period 
− 
Duration of mechanical 
ventilation during the 
Evaluation Period 
Alignment of language presented in the 
Pediatric Investigation Plan.  
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
AEDs over the Evaluation 
Period 
− 
Absolute and relative 
duration of ventilation 
during the treatment with 
BRV 
− 
Absolute and relative 
duration of ventilation 
during the treatment with 
other AEDs 
 
Section 5.1 
For the Exploratory Cohort (first 
step), enrolled subjects will receive 
one or multiple therapeutic doses of 
MDZ (dose of MDZ is at the 
discretion of the Investigator) prior 
to receiving BRV.  
For the Exploratory Cohort (first 
step), enrolled subjects will receive 
one or multiple therapeutic doses or 
continuous infusion of MDZ (dose 
and dosing frequency of MDZ are at 
the discretion of the Investigator) 
prior to receiving BRV.  
Dose frequency and continuous infusion are 
also at the discretion of the Investigator.  
Section 5.1 
The iv dose of BRV selected for the 
Confirmatory Cohorts will be 
determined by the evaluation of 
BRV plasma concentrations from the 
Exploratory Cohort to be within the 
range of plasma concentrations 
observed in children ≥1 month old 
who received 4mg/kg/day. 
The iv dose of BRV selected for the 
Confirmatory Cohorts will be 
determined by the evaluation of BRV 
plasma concentrations from the 
Exploratory Cohort, as well as by 
previous PK modeling of N01263 
data, to be within the range of plasma 
concentrations observed in children 
≥1 month old who received 
4mg/kg/day.  
Per agency recommendation, clarification that 
BRV dose and dosing frequency is also 
determined by previous PK modeling of 
N01263 data.  
 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 5.1 
Not applicable 
The recommendation to confirm or 
adjust the originally calculated BRV 
dose of the Confirmatory Cohorts of 
study N01349 will be given by the 
DMC after review of PK and safety 
data of the Exploratory Cohort. 
Clarification of DMC participation in 
determination of Confirmatory Cohort dosage. 
Section 5.1 
Not applicable 
Blood samples for routine assay of 
hematology, biochemistry, liver 
enzymes, and endocrinology will be 
collected in line with Section 13.2 of 
the “Ethical Considerations for 
Clinical Trials on Medicinal Products 
Conducted with the Paediatric 
Population” (European Union 
Commission ad hoc group, 2008), and 
according to the schedule of study 
assessments in Table 5-1 (Exploratory 
Cohort) and Table 5-2 (Confirmatory 
Cohorts). The local laboratories will 
perform the routine analysis of blood 
samples. For Screening and 
determination of eligibility, use of 
laboratory data acquired prior to 
Screening per standard of care inside 
or outside the study site within 36 
hours prior to the start of the 
Evaluation Period is allowed.     
Movement of text from Section 5.1.2 to Section 
5.1, since information applied to both cohorts.  
Blood sampling guidance.  
Laboratory assessments are allowed to be 
administered at a separate site.  
Allowance of use of standard of care laboratory 
data.  
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Section 5.1 
Not applicable  
Paragraphs 17 to 21 were moved from 
Section 5.1.2 to Section 5.1.  
Text was moved to Section 5.1 since 
information applied to both cohorts.  
Section 5.1 
The independent central reader will 
be blinded from concomitant AED 
treatment that the subject has 
received. 
The independent central reader will 
be blinded from site-specific 
information and the subject’s medical 
history. 
Blinding clarification.  
Section 5.1 
Not applicable  
Interruption of the VEEG is allowed 
up to 30 minutes per day. Depending 
on medical needs related to standard 
of care (eg, MRIs to be performed), 
interruptions longer than this are 
acceptable. However, every effort 
should be made to avoid VEEG 
interruption of the 2-hour Baseline 
VEEG and during the first 3 hours 
after the start of the initial BRV 
administration for the Confirmatory 
Cohorts. 
Based on Investigator feedback, neonates with 
hypoxic ischemic encephalopathy may 
disconnect from the EEG for other assessments, 
therefore interruptions exist and are allowed. 
Section 5.1.1 
For the Exploratory Cohort, at least 6 
subjects who do not have adequate 
seizure control after receiving 1 or 
2 doses of PB (total therapeutic 
administered dose of 20 to 40mg/kg; 
dosing regimen at the Investigator’s 
discretion) will be enrolled and 
dosed with one or multiple 
therapeutic doses of MDZ (dose of 
MDZ is at the discretion of the 
For the Exploratory Cohort, at least 6 
subjects who do not have adequate 
seizure control after receiving 1 to 
3 doses of PB (PB treatment may 
have started prior to the subject’s 
admission into the study site; total 
therapeutic administered dose of 20 to 
40mg/kg; dosing regimen at the 
Investigator’s discretion) will be 
enrolled and dosed with one or 
Dose frequency and continuous infusion are 
also at the discretion of the Investigator.  
Based on Investigator feedback, the total PB 
dose of 20 to 40mg/kg may be administered 
over 3 separate doses. PB treatment is 
permitted to start prior to subject’s admission 
into the study.  
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Investigator). Phenobarbital 
treatment must be discontinued prior 
to entering the Evaluation Period. 
Approximately 3 hours after the 
MDZ dosing, an initial low dose of 
BRV (0.5mg/kg [bid]) will be 
administered according to the 
standard of care.  
 
multiple therapeutic doses of MDZ 
(dose and dosing frequency of MDZ 
are at the discretion of the 
Investigator). Phenobarbital treatment 
must be discontinued prior to entering 
the Evaluation Period. 
Approximately 3 hours after the 
initiation of MDZ dosing, an initial 
low dose of BRV (0.5mg/kg [bid]) 
will be administered according to the 
standard of care.  
Section 5.1.1 
The first iv dose of PB (standard of 
care) can be administered between 
36 hours and 2 hours prior to the first 
administration of MDZ (depending 
on the number of PB doses and time 
between PB doses and the interval 
between PB treatment and first 
administration of MDZ). The initial 
PB treatment may have been 
administered prior to the subject’s 
enrollment in the study. 
The Screening Period is up to 36 
hours prior to the first administration 
of MDZ (depending on the number of 
PB doses and time between PB doses 
and the interval between PB treatment 
and first administration of MDZ). The 
PB treatment may have been 
administered prior to the subject’s 
enrollment in the study and/or at a 
location other than the study site. 
PB treatment is permitted to start prior to 
subject’s admission into the study, as well as 
allowed to be administered at a separate site 
prior to the study admittance.  
Section 5.1.1 
Baseline Period (included in the 
Screening Period): 2 hours 
immediately prior to the start of 
MDZ infusion. The occurrence of 
ENS during the 2-hour period must 
be confirmed either by the local or 
Baseline Period (included in the 
Screening Period): 2 hours 
immediately prior to the start of MDZ 
infusion. The occurrence of ENS 
during the 2-hour Baseline Period 
must be confirmed either by the local 
or central VEEG reader prior to drug 
Permitted use of EEG traces recorded before 
parents consented for the determination of the 
Baseline EEG.  
 
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central VEEG reader prior to the 
start of MDZ treatment.  
administration. Preferably, the central 
VEEG reader should confirm the 
required ENS. Video-EEGs that are 
acquired per standard of care prior to 
consenting and meet study-specific 
technical and quality requirements 
(eg, ability for immediate cloud-based 
central review) can be used as part of 
the Baseline assessment VEEG.  
Sections 
5.1.1,  8.1.3 
Not applicable 
The first MDZ infusion marks the 
starting point of the Evaluation 
Period.  
Clarification of the initiation of the Evaluation 
Period. 
Section 5.1.1 
Subjects will receive iv MDZ (one or 
multiple therapeutic doses; MDZ 
dose is at the discretion of the 
Investigator). 
Subjects will receive iv MDZ (one or 
multiple therapeutic doses or 
continuous infusion; MDZ dose and 
dosing frequency are at the discretion 
of the Investigator). 
Dose frequency and continuous infusion are 
also at the discretion of the Investigator.  
Section 5.1.1 
Following the first BRV infusion, 3 
to 6 PK blood microsamples 
(65µL/sample) will be collected 
during the 48-hour Evaluation Period 
from each subject for the 
determination of plasma 
concentrations of BRV and its 
metabolites, as described in Table 5-
4. 
Following the first BRV infusion, 3 to 
6 PK blood microsamples 
(60µL/sample) will be collected 
during the 48-hour Evaluation Period 
from each subject for the 
determination of plasma 
concentrations of BRV and its 
metabolites, as described in Table 5-
4. 
Volume of microsample tubes is 60 µL.  
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Section 5.1.2 
For the Confirmatory Cohorts, 
enrollment will only start after the 
dosing of BRV is determined based 
on the PK findings of the 
Exploratory Cohort. A total of at 
least 36 subjects without adequate 
seizure control after receiving 1 or 
2 doses of PB (total therapeutic 
administered dose of 20 to 40mg/kg; 
dosing regimen at the Investigator’s 
discretion) will enter the 
Confirmatory Cohorts. 
For the Confirmatory Cohorts, 
enrollment will only start after the 
dosing of BRV is determined based 
on the PK findings of the Exploratory 
Cohort and an existing PK model 
from N01263. A total of at least 36 
subjects without adequate seizure 
control after receiving 1 to 3 doses of 
PB (PB treatment may have started 
prior to the subject’s admission into 
the study site; total therapeutic 
administered dose of 20 to 40mg/kg; 
dosing regimen at the Investigator’s 
discretion) will enter the 
Confirmatory Cohorts. 
Based on Investigator feedback, the total PB 
dose of 20 to 40mg/kg may be administered 
over 3 separate doses.  
Dosing frequency is also at the discretion of the 
Investigator. Per agency recommendation, 
clarification that BRV dose and dosing 
frequency is also determined by previous PK 
modeling of N01263 data. 
Section 5.1.2 
The first iv dose of PB (standard of 
care) can be administered between 
36 hours and 2 hours prior to the first 
administration of MDZ (depending 
on the number of PB doses and time 
between PB doses and the interval 
between PB treatment and first 
administration of MDZ). The initial 
PB treatment may have been 
administered prior to the subject’s 
enrollment in the study. 
The Screening Period is up to 36 
hours prior to the first administration 
of BRV (depending on the number of 
PB doses and time between PB doses 
and the interval between PB treatment 
and first administration of BRV). The 
PB treatment may have been 
administered prior to the subject’s 
enrollment in the study and/or at a 
location other than the study site. 
PB treatment is permitted to start prior to 
subject’s admission into the study, as well as 
allowed to be administered at a separate site 
prior to the study admittance. 
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Section 5.1.2 
− 
Baseline Period (included in 
the Screening Period): 
2 hours immediately prior to 
the start of BRV infusion. 
The occurrence of ENS 
during this 2 hour period 
must be confirmed either by 
the local or central VEEG 
reader prior to the start of 
MDZ treatment.  
− 
Baseline Period (included in 
the Screening Period): 
2 hours immediately prior to 
the start of BRV infusion. 
The occurrence of ENS 
during the 2-hour Baseline 
Period must be confirmed 
either by the local or central 
VEEG reader prior to drug 
administration. Preferably, 
the central VEEG reader 
should confirm the required 
ENS. Video-EEGs that are 
acquired per standard of care 
prior to consenting and meet 
study-specific technical and 
quality requirements (eg, 
ability for immediate cloud-
based central review) can be 
used as part of the Baseline 
assessment VEEG.  
Permitted use of EEG traces recorded before 
parents consented for the determination of the 
Baseline EEG.  
 
Sections 
5.1.2, 8.2.3 
Not applicable 
The first administration of BRV 
marks the starting point of the 
Evaluation Period.  
Clarification of the initiation of the Evaluation 
Period. 
Section 5.1.2 
The BRV dose for subjects in the 
Confirmatory Cohorts will be 
determined based on the results of 
the PK analysis of the Exploratory 
Cohort (predicted to be 
The BRV dose for subjects in the 
Confirmatory Cohorts will be 
determined based on the results of the 
PK analysis of the Exploratory Cohort 
(predicted to be approximately the 
Per agency recommendation, clarification that 
BRV dose and dosing frequency is also 
determined by previous PK modeling of 
N01263 data. 
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approximately the BRV plasma 
concentrations in the same range as 
those observed at the highest 
recommended dose in older children 
and adults who receive BRV 
200mg/day). 
BRV plasma concentrations in the 
same range as those observed at the 
highest recommended dose in older 
children and adults who receive BRV 
200mg/day), as well as based on an 
existing PK model from N01263. 
Section 5.1.2 
Following the first BRV infusion, 6 
PK blood microsamples 
(65µL/sample) will be collected 
during the 96-hour Evaluation Period 
for each subject for the 
determination of plasma 
concentrations of BRV and its 
metabolites, as described in Table 5-
5. 
Following the first BRV infusion, 6 
PK blood microsamples 
(60µL/sample) will be collected 
during the 96-hour Evaluation Period 
for each subject for the determination 
of plasma concentrations of BRV and 
its metabolites, as described in Table 
5-5. 
Volume of microsample tubes is 60 µL. 
Section 5.1.2 
• 
Down-Titration Period (up 
to 1 week): A 
Down-Titration Period of up 
to 1 week is recommended 
for subjects in the 
Confirmatory Cohorts who 
do not proceed to the BRV 
Extension Period, or start the 
BRV Extension Period but 
do not enter the long-term 
study. 
• 
Down-Titration Period (up to 
1 week): A Down-Titration 
Period of up to 1 week is 
recommended for subjects in 
the Confirmatory Cohorts 
who discontinue BRV 
treatment prior to completion 
of the Evaluation Period, who 
do not proceed to the BRV 
Extension Period, or start the 
BRV Extension Period but do 
not enter the long-term study. 
Recommendations for subjects discontinuing 
BRV treatment. 
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Section 5.1.2, 
Table 5-2 
footnote b 
Not applicable 
Subjects discontinuing BRV 
treatment during the Evaluation 
Period should start the Down-
Titration Period while completing the 
Evaluation Period in parallel for the 
full 96 hours.  
Recommendations for subjects discontinuing 
BRV treatment. 
Table 5-1 
footnote c, 
Table 5-2 
footnote d 
c 
The occurrence of ENS during 
the 2-hour period must be confirmed 
either by the local or central VEEG 
reader, prior to the start of MDZ 
treatment.  
c 
The occurrence of ENS during the 
2-hour Baseline Period must be 
confirmed either by the local or 
central VEEG reader prior to drug 
administration. Preferably, the central 
VEEG reader should confirm the 
required ENS.  
Permitted use of EEG traces recorded before 
parents consented for the determination of the 
Baseline EEG.  
 
Table 5-1 
footnote d 
Not applicable  
d      Measurement of body weight is 
optional at 24 and 48 hours. Dosage 
of BRV during the Evaluation Period 
will be based on the subject’s weight 
measured prior to the start of the first 
BRV administration. However, 
dosage calculation can be adjusted to 
a more recent weight measurement, 
upon discretion of the Investigator, if 
weight is measured during the 
Evaluation Period. 
Clarification of timepoints for weight 
measurements. 
 
Table 5-1 
footnote f, 
Table 5-2 
footnote h 
Not applicable  
f        Video-EEGs that are acquired per 
standard of care prior to consenting 
and meet study-specific technical and 
quality requirements can be used as 
Permitted use of EEG traces recorded before 
parents consented for the determination of the 
Baseline EEG.  
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part of the Baseline assessment 
VEEG. 
Table 5-1 
footnote g 
g     Following the first BRV 
infusion, 3 to 6 blood microsamples 
(65µL/sample) will be collected 
from each subject in the Exploratory 
Cohort. 
g     Following the first BRV infusion, 
3 to 6 blood microsamples 
(60µL/sample) will be collected from 
each subject in the Exploratory 
Cohort. 
Volume of microsample tubes is 60 µL. 
Table 5-1 
footnote i, 
Table 5-2 
footnote k 
Not applicable  
i     For Screening and determination 
of eligibility, use of laboratory data 
acquired prior to Screening per 
standard of care inside or outside the 
study site within 36 hours prior to the 
start of the Evaluation Period is 
allowed.    
Allowance of use of standard of care laboratory 
data.  
Table 5-2 
footnote e 
Not applicable  
e      Measurement of body weight is 
optional at 24, 48, 72, and 96 hours. 
Dosage of BRV during the Evaluation 
Period will be based on the subject’s 
weight measured prior to the start of 
the first BRV administration. 
However, dosage calculation can be 
adjusted to a more recent weight 
measurement, upon discretion of the 
Investigator, if weight is measured 
during the Evaluation Period. 
Clarification of timepoints for weight 
measurements. 
 
Table 5-2 
footnote i  
i      Following the first BRV 
infusion, 6 blood microsamples 
(65µL/sample) will be collected 
i      Following the first BRV infusion, 
6 blood microsamples (60µL/sample) 
Volume of microsample tubes is 60 µL. 
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during the Evaluation Period from 
each subject. 
will be collected during the 
Evaluation Period from each subject. 
Table 5-3 
footnote a  
a       i     For Screening and determination of eligibility, 
use of laboratory data acquired prior to Screening per 
standard of care inside or outside the study site within 36 
hours prior to the start of the Evaluation Period is 
allowed.A Down-Titration Period of up 
to 1 week applies only to subjects in 
the Confirmatory Cohorts. The 
Down-Titration Period is 
recommended for subjects who do 
not proceed to the BRV Extension 
Period, or start the BRV Extension 
Period but do not enter the long-term 
study.  
 
a        A Down-Titration Period of up to 
1 week applies only to subjects in the 
Confirmatory Cohorts. The Down-
Titration Period is recommended for 
subjects who discontinue BRV 
treatment prior to completion of the 
Evaluation Period, who do not 
proceed to the BRV Extension Period, 
or start the BRV Extension Period but 
do not enter the long-term study. 
Subjects discontinuing BRV 
treatment during the Evaluation 
Period can continue assessments 
pertaining to the Evaluation Period, 
except the collection of blood 
microsamples for the determination of 
BRV plasma concentrations. Those 
subjects should start the Down-
Titration Period in parallel to 
completing the Evaluation Period.  
Recommendations for subjects discontinuing 
BRV treatment. 
Section 5.4.2 
The doses planned to be applied in 
this study are based on the available 
data in 96 pediatric subjects (overall, 
1 month to 17 years of age with the 
following number of subjects per 
pediatric age group: 1 month to 
<2 years of age, 29 subjects; 2 years 
The doses planned to be applied in 
this study are based on pediatric data 
collected in N01263 subjects (overall 
96 subjects in the age range of 1 
month to 17 years with the following 
number of subjects per pediatric age 
group: 1 month to <2 years of age, 
Clarification of dosage selection.  
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to <6 years of age, 26 subjects; 
6 years to <12 years of age, 
24 subjects; 12 years to <16 years of 
age, 17 subjects). 
29 subjects; 2 years to <6 years of 
age, 26 subjects; 6 years to <12 years 
of age, 24 subjects; 12 years to 
<16 years of age, 17 subjects). 
Section 5.4.2 
The dose of BRV to be administered 
in the Confirmatory Cohorts will be 
determined by the evaluation of 
plasma samples collected in the 
Exploratory Cohort and should not 
exceed the range of plasma 
concentrations observed in children 
≥1 month old who received BRV 
4mg/kg/day. 
The dose of BRV to be administered 
in the Confirmatory Cohorts will be 
determined by the evaluation of 
plasma samples collected in the 
Exploratory Cohort, as well as by the 
PK modeling of N01263 data 
described above, and should not 
exceed the range of plasma 
concentrations observed in children 
≥1 month old who received BRV 
4mg/kg/day. The plasma 
concentration of BRV 4mg/kg/day for 
neonates is predicted to be 
approximately equivalent to the 
plasma concentrations observed in 
adults who receive BRV 200mg/day. 
The dose in neonates to reach the 
same plasma concentrations will be 
confirmed or adapted upon 
completion of enrollment and analysis 
of PK and safety data from the 
Exploratory Cohort involving the 
DMC. The BRV dose used in the 
Confirmatory Cohorts will be based 
Per agency recommendation, clarification that 
BRV dose and dosing frequency is also 
determined by previous PK modeling of 
N01263 data. 
Clarification of DMC participation in 
determination of Confirmatory Cohort dosage. 
 
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on recommendations made by the 
DMC. 
Section 6.1 
2.Confirmation on VEEG of 
≥2 minutes of cumulative ENS or ≥3 
identifiable ENS within the 2 hours 
prior to entering the Evaluation 
Period (ENS is defined as a seizure 
lasting for at least 10 seconds on 
VEEG), despite receiving PB (total 
therapeutic administered dose of 
20 to 40mg/kg) for the treatment of 
repeated seizures.  
2a. Confirmation on VEEG of 
≥2 minutes of cumulative ENS or ≥3 
identifiable ENS within the 2 hours 
prior to entering the Evaluation 
Period (ENS is defined as a seizure 
lasting for at least 10 seconds on 
VEEG), despite receiving PB (total 
therapeutic administered dose of 20 to 
40mg/kg) for the treatment of 
repeated seizures.  
 
The occurrence of ENS during the 2-
hour Baseline Period must be 
confirmed either by the local or 
central VEEG reader prior to drug 
administration. Preferably, the central 
VEEG reader should confirm the 
required ENS.  
Local and central reader preference 
clarification.  
Section 6.2  
1.  Subject received AED treatment 
(other than the required 1 or 2 doses 
of PB [total therapeutic administered 
dose of 20 to 40mg/kg] for the 
treatment of repeated seizures) prior 
to entering the Evaluation Period. 
1a.  Subject received AED treatment 
(other than the required 1 to 3 doses 
of PB [total therapeutic administered 
dose of 20 to 40mg/kg] for the 
treatment of repeated seizures) prior 
to entering the Evaluation Period. 
Based on Investigator feedback, the total PB 
dose of 20 to 40mg/kg may be administered 
over 3 separate doses. 
Section 6.2 
8. Subject has conjugated bilirubin 
levels >2mg/dL. 
8a. Subject has direct (conjugated) 
bilirubin levels >2mg/dL. 
Language correction.  
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Section 6.3 
4. Subject has conjugated bilirubin 
levels >2mg/dL. 
4a. Subject has direct (conjugated) 
bilirubin levels >2mg/dL. 
Language correction.  
Section 6.3.1 
• 
Subject has conjugated bilirubin 
>2mg/dL. 
• 
Subject has direct (conjugated) 
bilirubin >2mg/dL. 
Language correction.  
Section 7.2 
Subjects in the Exploratory Cohort 
will be dosed with iv MDZ (dosing 
of MDZ is at the discretion of the 
Investigator). 
Subjects in the Exploratory Cohort 
will be dosed with iv MDZ (dosing 
and dosing frequency of MDZ are at 
the discretion of the Investigator). 
Dose frequency and continuous infusion are 
also at the discretion of the Investigator.  
Section 8.1.1 
The first iv dose of PB (standard of 
care) can be administered between 
36 hours and 2 hours prior to the first 
administration of MDZ (depending 
on the number of PB doses and time 
between PB doses and the interval 
between PB treatment and first 
administration of MDZ). 
The Screening Period is up to 36 
hours prior to the first administration 
of MDZ (depending on the number of 
PB doses and time between PB doses 
and the interval between PB treatment 
and first administration of MDZ). 
PB treatment is permitted to start prior to 
subject’s admission into the study, as well as 
allowed to be administered at a separate site 
prior to the study admittance. 
Sections 
8.1.1, 8.2.1 
The initial PB treatment may have 
started prior to the subject’s 
admission to the study.  
The PB treatment may have started 
prior to the subject’s admission to the 
study and/or at a location other than 
the study site but should be completed 
prior to the 2-hour Baseline Period.  
PB treatment is permitted to start prior to 
subject’s admission into the study, as well as 
allowed to be administered at a separate site 
prior to the study admittance. 
Section 8.1.2 
Not applicable 
Video-EEGs that are acquired per 
standard of care prior to consenting 
and meet study-specific requirements 
(eg, ability for immediate cloud-based 
Permitted use of EEG traces recorded before 
parents consented for the determination of the 
Baseline EEG. 
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central review) can be used as part of 
the Baseline assessment VEEG. 
Section 8.1.2 
The occurrence of ENS during this 
2-hour period must be confirmed 
either by the local or central VEEG 
reader prior to the start of MDZ 
treatment. 
The occurrence of ENS during the 2-
hour Baseline Period must be 
confirmed either by the local or 
central VEEG reader prior to drug 
administration. Preferably, the central 
VEEG reader should confirm the 
required ENS. 
Permitted use of EEG traces recorded before 
parents consented for the determination of the 
Baseline EEG.  
 
Section 8.1.2, 
8.2.2 
Verification of inclusion/exclusion 
criteria. Confirmation on VEEG of 
≥2 minutes of cumulative ENS or ≥3 
identifiable ENS within the 2 hours 
prior to entering the Evaluation 
Period (ENS is defined as a seizure 
lasting for at least 10 seconds on 
VEEG), despite PB treatment  
Verification of inclusion/exclusion 
criteria. Confirmation on VEEG of 
≥2 minutes of cumulative ENS or ≥3 
identifiable ENS within the 2 hours 
prior to entering the Evaluation 
Period (ENS is defined as a seizure 
lasting for at least 10 seconds on 
VEEG), despite PB treatment prior to 
Baseline 
PB treatment is permitted to start prior to 
subject’s admission into the study, as well as 
allowed to be administered at a separate site 
prior to the study admittance.  
Section 8.1.2 
Not applicable  
Baseline laboratory measurements 
will be performed by local 
laboratories unless historical data is 
available. Historical safety laboratory 
assessments, previously collected as 
standard of care, may be accepted 
from referring hospitals as Baseline 
measurement if performed 36 hours 
prior to the start of the Evaluation 
Period. In this case, test results will be 
Allowance of use of standard of care laboratory 
data.  
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considered medical history. Prior 
laboratory assessment results should 
already be available at Baseline and 
verified prior to initiation of the MDZ 
infusion. 
Section 8.1.3 
• 
Body weight (24 and 48 hours)  
• 
Body weight (optional [at 24 and 
48 hours]; dosage of BRV during 
the Evaluation Period will be 
based on the subject’s weight 
measured prior to the start of the 
first BRV administration. 
However, dosage calculation can 
be adjusted to a more recent 
weight measurement, upon 
discretion of the Investigator, if 
weight is measured during the 
Evaluation Period) 
Clarification of timepoints for weight 
measurements. 
 
Sections 
8.1.4, 8.2.4 
Extension Period Visit 2 will be 
performed on the same day when the 
subject enters the long-term study 
(see Section 8.1.3.2).  
Extension Period Visit 2 will be 
performed on the same day when the 
subject enters the long-term study 
N01266 (see Section 8.1.3.2). If study 
N01266 is performed outside the 
N01349 hospital, an interval of up to 
3 days between the N01349 EPV2 
and N01266 Entry Visit is allowed. 
Clarification of visit intervals.  
Section 8.2.1 
The Screening Period (up to 36 
hours) will be from the signing and 
dating of the written ICF by the 
The Screening Period will be from the 
signing and dating of the written ICF 
by the parent(s) or legal 
Elimination of repetition.  
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Section 
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parent(s) or legal representative(s) of 
the subject to the end of the Baseline 
Period. 
representative(s) of the subject to the 
end of the Baseline Period. 
Section 8.2.1 
The first iv dose of PB (standard of 
care) can be administered between 
36 hours and 2 hours prior to the first 
administration of BRV (depending 
on the number of PB doses and time 
between PB doses and the interval 
between PB treatment and first 
administration of BRV). 
The Screening Period is up to 36 
hours prior to the first administration 
of BRV (depending on the number of 
PB doses and time between PB doses 
and the interval between PB treatment 
and first administration of BRV). 
PB treatment is permitted to start prior to 
subject’s admission into the study, as well as 
allowed to be administered at a separate site 
prior to the study admittance. 
Section 8.2.2 
The occurrence of ENS during this 
2-hour period must be confirmed 
either by the local or central VEEG 
reader prior to the start of BRV 
treatment. 
The occurrence of ENS during the 2-
hour Baseline Period must be 
confirmed either by the local or 
central VEEG reader prior to drug 
administration. Preferably, the central 
VEEG reader should confirm the 
required ENS. Video-EEGs that are 
acquired per standard of care prior to 
consenting and meet study-specific 
technical and quality requirements 
(eg, ability for immediate cloud-based 
central review) can be used as part of 
the Baseline assessment VEEG.  
Permitted use of EEG traces recorded before 
parents consented for the determination of the 
Baseline EEG.  
 
Section 8.2.2 
Not applicable  
Baseline laboratory measurements 
will be performed by local 
laboratories unless historical data is 
available. Historical safety laboratory 
Allowance of use of standard of care laboratory 
data. 
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Section 
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assessments, previously collected as 
standard of care, may be accepted 
from referring hospitals as Baseline 
measurement if performed 36 hours 
prior to the start of the Evaluation 
Period. In this case, test results will be 
considered medical history. Prior 
laboratory assessment results should 
already be available at Baseline and 
verified prior to initiation of BRV 
administration.   
Section 8.2.3 
Not applicable  
If subjects in the Confirmatory Cohort 
receive <8 BRV doses, those subjects 
are allowed to continue study 
participation and complete study 
assessments per Table 17-2, with the 
exception of PK blood sampling. 
Those subjects should start the Down-
Titration Period while completing the 
Evaluation Period in parallel for the 
full 96 hours.  
Recommendations for subjects discontinuing 
BRV treatment. 
Section 8.2.3 
• 
Body weight (at 24, 48, 72 and 
96 hours).  
• 
Body weight (optional [at 24, 48, 
72 and 96 hours]; dosage of BRV 
during the Evaluation Period will 
be based on the subject’s weight 
measured prior to the start of the 
first BRV administration. 
However, dosage calculation can 
be adjusted to a more recent 
Clarification of timepoints for weight 
measurements. 
 
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Section 
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weight measurement, upon 
discretion of the Investigator, if 
weight is measured during the 
Evaluation Period) 
Section 8.2.5 
A Down-Titration Period of up to 1 
week is recommended for subjects 
who complete the Evaluation Period, 
but do not enter the BRV Extension 
Period, or start the BRV Extension 
Period but do not continue into the 
long-term study for any reason. 
A Down-Titration Period of up to 1 
week is recommended for subjects 
who complete the Evaluation Period, 
but do not enter the BRV Extension 
Period, discontinue BRV during the 
Evaluation Period, or start the BRV 
Extension Period but do not continue 
into the long-term study for any 
reason. 
Recommendations for subjects discontinuing 
BRV treatment. 
Section 9.1 
For the determination of plasma 
concentrations of BRV and BRV 
metabolites, up to 6 blood 
microsamples (65μL/sample) will be 
collected per subject in the 
Exploratory (3 to 6 blood 
microsamples) and Confirmatory 
Cohorts (up to 6 blood 
microsamples) at 3 predetermined 
timepoints per day. An additional 
microsample (65μL) will be 
collected per subject for the 
determination of plasma 
concentrations of concomitant AEDs 
(PB and PHT). 
For the determination of plasma 
concentrations of BRV and BRV 
metabolites, up to 6 blood 
microsamples (60μL/sample) will be 
collected per subject in the 
Exploratory (3 to 6 blood 
microsamples) and Confirmatory 
Cohorts (up to 6 blood microsamples) 
at 3 predetermined timepoints per 
day. An additional microsample 
(60μL) will be collected per subject 
for the determination of plasma 
concentrations of concomitant AEDs 
(PB and PHT). 
Volume of microsample tubes is 60 µL. 
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Section 
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Sections 10.1, 
13.5.1 
• 
Absolute reduction and 
proportion of clinical seizures 
correlated with continuous 
VEEG from Baseline to the end 
of the 96-hour Evaluation 
Period, and at each of the 3-hour 
intervals 
• 
Absolute and percent difference 
in clinical seizures at the end of 
the 24-hour Evaluation Period 
from Baseline for neonates with 
motor seizures at the time of 
inclusion 
Alignment of language presented in the 
Pediatric Investigation Plan.  
Section 11.1.1 • 
Potential drug-induced liver 
injury as indicated by: 
− 
Conjugated bilirubin 
>2mg/dL 
• 
Potential drug-induced liver 
injury as indicated by: 
− 
Direct (conjugated) bilirubin 
>2mg/dL 
Language correction.  
Section 11.1.2 In line with GCP, from the signing 
of the ICF, the Investigator will 
record any AEs that occur to the 
subject, and will keep detailed 
records of all AEs that occur. All 
AEs will be recorded daily in each 
subject’s medical notes. Serious 
AEs, AEs that are considered related 
to the medicinal (investigational) 
product, AEs leading to 
discontinuation, infusion site 
reactions, or AEs considered by the 
Investigator to be critical to the 
safety evaluation of the protocol will 
also be recorded on the Adverse 
Event eCRF. 
In line with GCP, from the signing of 
the ICF, the Investigator will evaluate 
the subject for occurrence of any AEs 
based on continued observation and 
medical notes throughout the study. 
Serious AEs, AEs that are considered 
related to the medicinal 
(investigational) product, AEs leading 
to discontinuation, BRV infusion site 
reactions, or AEs considered by the 
Investigator to be critical to the safety 
evaluation of the protocol will also be 
recorded on the Adverse Event eCRF. 
Adverse event recording clarification.  
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Section 
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Section 11.2 
Not applicable  
Blood samples will be collected in 
line with Section 13.2 of the “Ethical 
Considerations for Clinical Trials on 
Medicinal Products Conducted with 
the Paediatric Population” (European 
Union Commission ad hoc group, 
2008). 
Recommendations for subjects discontinuing 
BRV treatment. 
Section 11.2 
All laboratory measurements, 
including laboratory assessments for 
PDILI, will be performed by local 
laboratories.  
Laboratory measurements, including 
laboratory assessments for PDILI, 
will be performed by local 
laboratories unless historical data is 
available. Historical safety laboratory 
assessments, previously collected as 
standard of care, may be accepted 
from referring hospitals as Baseline 
measurement if performed 36 hours 
prior to the Evaluation Period.  
Allowance of use of standard of care laboratory 
data.  
Section 11.2 
As part of routine assessments 
performed by local laboratories, the 
parameters shown in Table 11-1 will 
be measured. 
 
As part of routine assessments 
performed by local laboratories, the 
parameters shown in Table 11-1 and 
Table 11-2 will be measured. 
 
Table addition.  
Table 11-3 
Conjugated bilirubin 
Direct (conjugate) bilirubin  
Language correction.  
Section 
11.2.1.3 
Not applicable  
Recommended testing is at the 
discretion of the Investigator and 
should be individualized 
Testing recommendation clarification.  
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Section 
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appropriately based on clinical 
situation. 
Section 11.3.8 Not applicable  
Withdrawal and rebound phenomena, 
if any, will be captured from data 
collected at the end of BRV exposure 
for subjects in both the Exploratory 
and Confirmatory Cohorts 
Text was relocated.  
Section 11.3.9 Numbers and percentage of subjects 
requiring mechanical ventilation at 
the time they are treated with BRV 
will be recorded from Baseline 
through the 48-hour Evaluation 
Period for the Exploratory Cohort 
and the 96-hour Evaluation Period 
for the Confirmatory Cohorts and 
compared between subjects that 
required BRV only and subjects 
treated with BRV and receiving 
rescue medication or other AEDs. 
Absolute and relative duration of 
ventilation at the time subjects are 
treated with BRV will be recorded 
over the Evaluation Period and 
compared between subjects treated 
with BRV only and subjects treated 
with BRV and receiving rescue 
medication or other AEDs. 
Numbers and percentage of subjects 
requiring mechanical ventilation will 
be recorded from Baseline through 
the 48-hour Evaluation Period for the 
Exploratory Cohort and the 96-hour 
Evaluation Period for the 
Confirmatory Cohort.  
Duration of mechanical ventilation 
will be recorded over the Evaluation 
Period.  
Alignment of language presented in the 
Pediatric Investigation Plan.  
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Section 
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Section 13.3 
Not applicable 
The analysis of the PK parameters for 
the Exploratory and Confirmatory 
Cohorts will include a sub-analysis 
for any concomitant use of 
hypothermia. 
Content consistency. Text was relocated.   
Section 13.4 
The primary cause of seizure (HIE, 
hemorrhage, or infarction; CNS 
malformations; CNS infections; 
undetermined causes) may also be 
used to categorize the safety review. 
The primary cause of seizure (eg, 
HIE, hemorrhage, or infarction; CNS 
malformations; CNS infections; 
undetermined causes) may also be 
used to categorize the safety review. 
Typographical change.  
Section 13.7 
Subjects in the Confirmatory 
Cohorts are withdrawn, are switched 
over to another AED treatment, prior 
to the Evaluation Period or are 
administered >1 dose of rescue 
medication (including BZDs) 
following the first 3 hours after 
initial BRV treatment started will be 
considered BRV nonresponders. 
Subjects in the Confirmatory Cohorts 
who drop out due to lack of BRV 
efficacy, are switched over to another 
AED treatment, or are administered 
>1 dose of rescue medication 
(including BZDs) following the first 
3 hours after initial BRV treatment 
started will be considered BRV 
nonresponders. 
Recommendations for subjects discontinuing 
BRV treatment. 
Section 13.8.1 Upon the completion of the 
Exploratory Cohort, the DMC will 
be provided with the summaries and 
the listings of PK and safety data for 
review (see Section 13.8.3).  
Upon the completion of the 
Exploratory Cohort, the DMC will be 
provided with the summaries and the 
listings of PK and safety data for 
review to make recommendations 
concerning the dosing of BRV in the 
Confirmatory Cohorts (see Section 
13.8.3). 
Clarification of DMC participation in 
determination of Confirmatory Cohort dosage. 
 
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Section 
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Section 14.1 
Not applicable  
An informed consenting process 
managed via telephone is allowed 
where applicable per local 
regulations. 
Allowance of telephone consenting process.  
References 
Not applicable 
European Union Commission ad hoc 
group. Recommendations of the ad 
hoc group for the development of 
implementing guidelines for Directive 
2001/20/EC relating to good clinical 
practice in the conduct of clinical 
trials on medicinal products for 
human use. Ethical Considerations for 
Clinical Trials on Medicinal Products 
Conducted with the Paediatric 
Population. 2008; 13.2. 
https://ec.europa.eu/health/sites/health
/files/files/eudralex/vol-
10/ethical_considerations_en.pdf. 
Reference addition.  
 
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Figure 5-1: Schematic overview of the study for the Exploratory Cohort 
 
BRV=brivaracetam; ICF=informed consent form; MDZ=midazolam; VEEG=(multichannel) video-electroencephalography 
Note: A continuous consent process will be followed. Parent(s) or legal representative(s) will be informed about the study as early as possible and asked to sign 
the ICF after the occurrence of seizures has been confirmed by VEEG. During the course of the study, parent(s) or legal representative(s) will be updated about 
the care of their neonate, and continuous consent will be ensured by meetings between the Investigator (or designee) and the subject’s parent(s) or legal 
representative(s). 
a The anticipated duration of the BRV Extension Period is up to 28 days of postnatal age (+7 days). 
b Subjects in the Exploratory Cohort will enter the Safety Follow-Up Period, if they complete the Evaluation Period or are discontinued from the BRV Extension 
Period. 
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For adjustment of dosing and time intervals, Figure 5-1 was changed to: 
Figure 5-1: Schematic overview of the study for the Exploratory Cohort  
 
BRV=brivaracetam; ICF=Informed Consent form; MDZ=midazolam; VEEG=(multichannel) video-electroencephalography 
Note: A continuous consent process will be followed. Parent(s) or legal representative(s) will be informed about the study as early as possible and asked to sign 
the ICF after the occurrence of seizures has been confirmed by VEEG. During the course of the study, parent(s) or legal representative(s) will be updated about 
the care of their neonate, and continuous consent will be ensured by meetings between the Investigator (or designee) and the subject’s parent(s) or legal 
representative(s). 
a The anticipated duration of the BRV Extension Period is up to 28 days of postnatal age (+7 days). 
b Subjects in the Exploratory Cohort will enter the Safety Follow-Up Period, if they complete the Evaluation Period or are discontinued from the BRV Extension 
Period. 
 
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Figure 5-2: Screening and Evaluation Periods (Exploratory Cohort) 
 
BRV=brivaracetam; ICF=informed consent form; MDZ=midazolam; PB=phenobarbital 
Note: The Screening Period is from signing and dating of the written ICF up to Cohort Assignment. The first iv dose of PB (standard of care) can be administered 
between 36 hours and 2 hours prior to the first administration of MDZ (depending on the number of PB doses and time between PB doses and the interval 
between PB treatment and first administration of MDZ). The PB treatment may have been administered prior to the subject’s enrollment in the study and/or at a 
location other than the designated site. 
a Treatment with MDZ will continue in parallel with BRV. 
b Subjects enrolled in the Exploratory Cohort will receive a therapeutic dose of MDZ (dose and dosing frequency of MDZ are at the discretion of the 
Investigator) prior to receiving BRV. Subsequently, an initial low dose of iv BRV will be administered. At the discretion of the Investigator, 3 additional iv 
BRV doses can be administered, up to a total of 4 iv BRV doses (0.5mg/kg twice daily [bid]), during the 48-hour Evaluation Period. 
c If seizures are adequately controlled with previous AED treatment per SOC, subjects will be considered screen failures and will not be permitted to enter the 
Evaluation Period. 
 
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For adjustment of dosing and time intervals, Figure 5-2 was changed to: 
Figure 5-2: Screening and Evaluation Periods (Exploratory Cohort) 
 
BRV=brivaracetam; ICF=Informed Consent form; MDZ=midazolam; PB=phenobarbital 
Note: The Screening Period is from signing and dating of the written ICF up to Cohort Assignment. The Screening Period is up to 36 hours prior to the first 
administration of MDZ (depending on the number of PB doses and time between PB doses and the interval between PB treatment and first administration of 
MDZ). The PB treatment may have been administered prior to the subject’s enrollment in the study and/or at a location other than the study site. 
a Treatment with MDZ will continue in parallel with BRV. 
b Subjects enrolled in the Exploratory Cohort will receive one or multiple therapeutic doses or continuous infusion of MDZ (dose and dose frequency of MDZ 
are at the discretion of the Investigator) prior to receiving BRV. Subsequently, an initial low dose of iv BRV will be administered. At the discretion of the 
Investigator, 3 additional iv BRV doses can be administered, up to a total of 4 iv BRV doses (0.5mg/kg twice daily [bid]), during the 48-hour Evaluation 
Period. 
c If seizures are adequately controlled with previous AED treatment per SOC, subjects will be considered screen failures and will not be permitted to enter the 
Evaluation Period. 
Continuous consent process 
Start of MDZ 
Treatmenta
Baseline
3 hours
Start of BRV
Administration 
Screening
(up to 36 hours)
Evaluation Period
(51 hours: 3 hours MDZ + 48 hours BRV)
Cohort 
Assignment
Screen Failurec
(PB responder)
Birth
PB 1
PB 2
(optional)
PB 3
(optional)
BRV Administration: 
Up to a total of 4 (1+3) iv BRV doses (0.5mg/kg bid)b
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Figure 5-3: Schematic overview of the study for the Confirmatory Cohorts 
BRV=brivaracetam; ICF=informed consent form; VEEG=(multichannel) video-electroencephalography 
Note: A continuous consent process will be followed. Parent(s) or legal representative(s) will be informed about the 
study as early as possible and asked to sign the ICF after the occurrence of seizures has been confirmed by VEEG. 
During the course of the study, parent(s) or legal representative(s) will be updated about the care of their neonate, 
and continuous consent will be ensured by meetings between the Investigator (or designee) and the subject’s 
parent(s) or legal representative(s). 
a The anticipated duration of the BRV Extension Period is up to 28 days of postnatal age (+7 days). 
For adjustment of dosing and time intervals, Figure 5-3 was changed to: 
Figure 5-3: Schematic overview of the study for the Confirmatory Cohorts 
BRV=brivaracetam; ICF=Informed Consent form; VEEG=(multichannel) video-electroencephalography 
Note: A continuous consent process will be followed. Parent(s) or legal representative(s) will be informed about the 
study as early as possible and asked to sign the ICF after the occurrence of seizures has been confirmed by VEEG. 
During the course of the study, parent(s) or legal representative(s) will be updated about the care of their neonate, 
and continuous consent will be ensured by meetings between the Investigator (or designee) and the subject’s 
parent(s) or legal representative(s). 
a The anticipated duration of the BRV Extension Period is up to 28 days of postnatal age (+7 days). 
 
Screening
(up to 36 hours)
Continuous consent process 
Evaluation Period
(96 hours)
BRV Extension Period
(up to an age of 28 +7 days a)
Down-Titration Period 
(up to 1 week)
Long-term Study (N01266; oral BRV)
Safety Follow-Up Period
(30 +/- 3 days)
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Figure 5-4: Screening and Evaluation Periods (Confirmatory Cohorts) 
 
AED=antiepileptic drug; BRV=brivaracetam; ICF=informed consent form; PB=phenobarbital 
Note: The Screening Period is from signing and dating of the written ICF up to Cohort Assignment. The first iv dose of PB (standard of care) can be administered 
between 36 hours and 2 hours prior to the first administration of BRV (depending on the number of PB doses and time between PB doses and the interval 
between PB treatment and first administration of BRV). The initial PB treatment may have been administered prior to the subject’s enrollment in the study. 
a Switching to another AED or addition of rescue medication should only occur following 3 hours after the first BRV administration. 
b If seizures are adequately controlled with previous AED treatment per SOC, subjects will be considered screen failures and will not be permitted to enter the 
Evaluation Period. 
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For adjustment of dosing and time intervals, Figure 5-4 was changed to: 
Figure 5-4: 
Screening and Evaluation Periods (Confirmatory Cohorts) 
 
AED=antiepileptic drug; BRV=brivaracetam; ICF=Informed Consent form; PB=phenobarbital 
Note: The Screening Period is from signing and dating of the written ICF up to Cohort Assignment. The Screening Period is up to 36 hours prior to the first 
administration of BRV (depending on the number of PB doses and time between PB doses and the interval between PB treatment and first administration of 
BRV). The PB treatment may have been administered prior to the subject’s enrollment in the study and/or at a location other than the study site. 
a Switching to another AED or addition of rescue medication should only occur following 3 hours after the first BRV administration. 
b If seizures are adequately controlled with AED treatment per SOC, subjects will be considered screen failures and will not be permitted to enter the Evaluation 
Period. 
 
Continuous consent process 
Screening 
(up to 36 hours)
Evaluation Period
(96 hours)
Start of BRV
Treatment
Baseline
Switch to other AEDa
Screen Failureb
(PB responder)
3 hours
Addition of rescue medicationa
Cohort 
Assignment
Birth
PB 1
PB 2
(optional)
PB 3
(optional)
BRV Treatment
(BRV dosing based on the results of the Exploratory Cohort)
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Table 11-1: Laboratory measurements 
Hematology 
Biochemistry 
Urinalysis 
Endocrinology 
Basophils 
Calcium 
Albumin 
TSH 
Eosinophils 
Chloride 
Bacteria 
T3 
Lymphocytes 
Potassium 
Glucose 
T4 
Atypical 
lymphocytes 
Sodium 
pH 
 
Monocytes 
Glucose 
RBC 
 
Neutrophils 
BUN 
WBC 
 
Hematocrit 
Creatine kinase 
 
 
Hemoglobin 
AST 
 
 
MCH 
ALT 
 
 
MCHC 
GGT 
 
 
MCV 
Total bilirubin 
 
 
Platelet count 
LDH 
 
 
RBC count 
Total cholesterol 
 
 
WBC count 
 
 
 
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; 
T3=triiodothyronine; T4=thyroxine; TSH=thyroid-stimulating hormone; WBC=white blood cell 
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For clarification of laboratory assessments, Table 11-1 was split into mandatory and optional 
measurements: 
Table 11-1: Mandatory laboratory measurements 
Hematology 
Biochemistry 
Basophils 
Calcium 
Eosinophils 
Chloride 
Lymphocytes 
Potassium 
Atypical lymphocytes 
Sodium 
Monocytes 
Glucose 
Neutrophils 
Urea/BUNa 
Hematocrit 
Creatine kinase 
Hemoglobin 
AST 
MCH 
ALT 
MCHC 
ALP 
MCV 
GGT 
Platelet count 
LDH 
RBC count 
Total bilirubin 
WBC count 
Direct (conjugated) bilirubin 
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 
a  Urea or BUN to be tested depending on the local lab´s standard panel for neonates. 
 
Table 11-2: Optional laboratory measurements 
Biochemistry 
Urinalysisb 
Endocrinologyc 
Total cholesterola 
Protein 
TSH 
 
Bacteria 
T4 
 
Glucose 
 
 
pH 
 
 
RBC 
 
 
WBC 
 
RBC=red blood cell; T4=thyroxine; TSH=thyroid-stimulating hormone; WBC=white blood cell 
a Total cholesterol to be measured if this is part of the local lab´s standard panel for neonates. 
b Urinalysis to be performed only if a urine sample was obtained for clinical purposes. 
c TSH and T4 to be recorded for the study only if measured for neonatal screening of congenital hypothyroidism 
prior to or during study participation. 
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17.4 
Protocol Amendment 4 
Rationale for the amendment 
The primary purpose of this nonsubstantial protocol amendment is to update the laboratory 
measurement section where creatinine was inadvertently not included as a mandatory laboratory 
measurement. Creatinine is needed for monitoring of renal function. Clarification for optional 
laboratory measurements has also been provided. 
Specific changes 
Change #1 
Table 11-1 
Creatinine has been added as a new laboratory parameter and in addition, the following footnote 
b was added:  
b  During the first days of life, creatinine will only be collected if the site assesses this parameter 
per standard of care. 
Change #2 
Table 11-2 Footnote b 
b 
Urinalysis to be performed only if a urine sample was obtained for clinical purposes. 
Has been changed to 
b 
Urinalysis to be performed only if a urine sample was obtained for clinical purposes. A urine 
dipstick is acceptable. 
 
 
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17.5 
Protocol Amendment 5 
Rationale for the amendment 
The purpose of this substantial amendment is to implement the changes from the agreed Pediatric 
Investigation Plan for BRV in order to help improve enrollment rate (to date, 1 subject has been 
enrolled). The primary change is to remove restriction in terms of concomitant medication by 
replacing PB only with SOC for the Exploratory Cohort and one or more of the following AEDs: 
PB, MDZ, PHT, LEV (≤60mg/kg/day) or LDC for the Confirmatory Cohort. Also, the age range 
has been modified. Additionally, subjects will be proposed to enroll into a new long-term follow-
up study. 
A brief list of modifications to the protocol include the following: 
• Age at enrollment modified 
• Phenobarbital no longer required as first line treatment prior to BRV; replaced by “ENS 
treatment per SOC (first line, second line, or subsequent treatment; choice of treatment, 
dose and dosing at the Investigator´s discretion)” for the Exploratory Cohort and “one or 
more of the following AEDs: PB, MDZ, PHT, LEV (≤60mg/kg/day) or LDC (first line, 
second line or subsequent treatment; dose and dosing at the Investigator´s discretion)” for 
the Confirmatory Cohorts 
• 2-hour Baseline EEG and 48-hour VEEG removed from the Exploratory Cohort; required 
ENS to be confirmed by the Investigator via local EEG  
• Duration of the 2-hour Baseline Period shortened to up to 1 hour for the Confirmatory 
Cohorts and separated by seizure activity: “at least 1 hour” for subjects with intermittent 
ENS and “up to 30 minutes” for subjects in status epilepticus 
• Definition of status epilepticus for neonates enrolled into this study was added 
• Treatment with “MDZ only” during the first 3 hours of the Evaluation Period removed 
from the Confirmatory Cohort; duration of the Evaluation Period hence shortened from 
51 to 48 hours 
• Historical control changed from “MDZ” to “one or more AED treatments”  
• The initiation of LEV treatment after the first time BRV is introduced is prohibited 
throughout the study for the Confirmatory Cohorts  
• Inclusion Criteria 2a and 3, Exclusion Criteria 1a and 2 modified 
• Use of concomitant medication and rescue medication adapted 
• PK variables split into “primary” and “other” PK variables 
• Safety variables categorized as “secondary safety variable” and “other safety variables” 
• Reference to N01266 removed since this study will be closed before the last N01349 
subject was able to participate in that study for 3 years. Those subjects may instead 
roll-over to EP0132. Study number replaced by generic term “long-term study” 
• Clarified that enrollment will be put on hold during the first DMC (that was always the 
plan but not explicitly mentioned in the protocol) 
• Marketing status of BRV updated 
 
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Specific changes 
Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
STUDY 
CONTACT 
INFORMAT-
ION 
Removed study physican 
 name, address, 
and contact information 
Added 
 relevant 
information 
Study physician has changed 
Section 1 
Summary 
Subjects will first receive 1 to 3 
doses of phenobarbital (PB) (total 
therapeutic administered dose of 
20 to 40mg/kg; dosing regimen at 
the Investigator’s discretion). If 
they do not have adequate seizure 
control after receiving PB, they 
may be enrolled into N01349, but 
they must stop PB treatment.  
Subjects will first receive 
antiepileptic drugs (AEDs) for the 
treatment of 
electroencephalographic neonatal 
seizures (ENS) (first-line, second-
line, or subsequent treatment, 
which may have started prior to 
the subject’s admission into the 
study site; dose and dosing 
regimen at the Investigator’s 
discretion). If they do not have 
adequate seizure control after the 
treatment with AEDs, they may be 
enrolled into N01349. 
PB no longer required as first-line 
treatment prior to BRV 
Section 1 
Summary 
For the Exploratory Cohort (first 
step), enrolled subjects will 
receive one or multiple doses or 
continuous infusion of a 
therapeutic dose of midazolam 
(MDZ) (dose and dosing 
frequency of MDZ is at the 
discretion of the Investigator) 
prior to receiving BRV 
For the Exploratory Cohort (first 
step), enrolled subjects will 
receive 1 or more AEDs per 
standard of care (SOC) for the 
treatment of ENS (first-line, 
second-line, or subsequent 
treatment; choice of treatment, 
dose, and dosing frequency is at 
the discretion of the Investigator) 
prior to receiving BRV 
Historical control changed from MDZ to “1 
or more AED treatments” 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 1 
Summary 
The primary objective of this 
study is to evaluate the PK of 
BRV in neonates who have 
seizures that are not adequately 
controlled with PB treatment, and 
to identify the optimal BRV dose 
(Exploratory Cohort) for the 
treatment of subjects enrolled into 
the Confirmatory Cohorts of this 
study. Secondary objectives 
include the evaluation of the 
short-term safety and tolerability 
of BRV in neonates and the 
evaluation of the efficacy of BRV 
in severe and nonsevere seizure 
burden (defined as total minutes 
of ENS per hour) in neonates with 
seizures that are not adequately 
controlled with PB treatment 
The primary objective of this study 
is to evaluate the PK of BRV in 
neonates who have seizures that 
are not adequately controlled with 
previous AED treatment, and to 
identify the optimal BRV dose 
(Exploratory Cohort) for the 
treatment of subjects enrolled into 
the Confirmatory Cohorts of this 
study. Secondary objectives 
include the evaluation of the 
short-term safety and tolerability 
of BRV in neonates and the 
evaluation of the efficacy of BRV 
in severe and nonsevere seizure 
burden (defined as total minutes of 
ENS per hour) in neonates with 
seizures that are not adequately 
controlled with previous AED 
treatment 
PB no longer required as first line treatment 
prior to BRV 
Section 1 
Summary 
Subjects must be of 34 weeks to 
less than 42 weeks of gestational 
age (GA) at birth and up to 28 
days of postnatal age at the time 
of enrollment.  
At enrollment, subjects must be at 
least 34 weeks of corrected 
gestational age (CGA). In 
addition, term neonates up to 
27 days of postnatal age (PNA) 
and preterm neonates up to 40 
weeks of postmenstrual age 
(PMA) and 27 days of PNA can be 
enrolled. 
Age at enrollment was modified 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 1 
Summary 
Subjects must have a confirmed 
diagnosis of ENS by multichannel 
video-electroencephalography 
(VEEG) of ≥2 minutes of 
cumulative ENS or ≥3 
identifiable ENS within the 
2 hours prior to entering the 
Evaluation Period (ENS is 
defined as a seizure lasting for at 
least 10 seconds on VEEG), 
despite receiving PB for the 
treatment of repeated seizures. 
The maximum study duration per 
subject will be up to 75 days, 
which consists of a Screening 
Period, Baseline Period, 
Evaluation Period, BRV 
Extension Period, Down-Titration 
Period (Confirmatory Cohorts 
only), and Safety Follow-Up 
Period. All subjects who 
participate in the BRV Extension 
Period must be offered entry into 
the long-term study N01266, if 
they meet the eligibility criteria. 
Before entering the long-term 
study, subjects must be on oral 
BRV 
Subjects must have a confirmed 
diagnosis of ENS by multichannel 
video-electroencephalography 
(VEEG) of ≥2 minutes of 
cumulative ENS or ≥3 identifiable 
ENS prior to entering the 
Evaluation Period (ENS is defined 
as a seizure lasting for at least 
10 seconds on VEEG), despite 
receiving AED treatment. The 
maximum study duration per 
subject will be up to 75 days, 
which consists of a Screening 
Period, Baseline Period 
(Confirmatory Cohorts only), 
Evaluation Period, BRV Extension 
Period, Down-Titration Period 
(Confirmatory Cohorts only), and 
Safety Follow-Up Period. All 
subjects who participate in the 
BRV Extension Period must be 
offered entry into a long-term 
study, if they meet the eligibility 
criteria. Before entering the long-
term study, subjects must be on 
oral BRV 
Clarification 
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Page 178 of 254 
Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 1 
Summary 
The PK variables are the plasma 
concentrations of BRV, the area 
under the curve (AUC), volume 
of distribution, and clearance of 
BRV in neonates. Further, PK 
assessments will include plasma 
concentrations of concomitant 
antiepileptic drugs (AEDs) (PB 
and phenytoin [PHT]). 
The PK variables are the plasma 
concentrations of BRV, the area 
under the curve (AUC), volume of 
distribution, and clearance of BRV 
in neonates. Further, PK 
assessments will include plasma 
concentrations of concomitant 
phenobarbital (PB) and phenytoin 
(PHT) if administered 
Clarification 
Section 1 
Summary 
The efficacy of BRV will be 
analyzed based on the following 
variables: 
The efficacy of BRV will be 
analyzed for the Confirmatory 
Cohorts based on the following 
variables: 
Clarification 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 1 
Summary 
A BRV responder is defined as a 
subject who achieves a reduction 
in seizure burden (ENS in 
minutes per hour), compared to 
the seizure burden measured 
during the 2-hour Baseline Period 
immediately prior to BRV 
administration, evaluated for a 
2-hour period starting 1 hour after 
the start of initial BRV treatment. 
Reduction in seizure burden is 
defined as at least 80% reduction 
in nonsevere seizure burden 
(nonsevere seizure burden is 
defined as ≤50% seizure activity 
on VEEG in any 30-minute 
timespan) or at least 50% 
reduction in severe seizure burden 
(severe seizure burden is defined 
as >50% seizure activity on 
VEEG in any 30-minute 
timespan); timespans of 30 
minutes refer to the following 
intervals within the 2-hour period: 
0 to ≤30 minutes, >30 to ≤60 
minutes, >60 to ≤90 minutes, and 
>90 to ≤120 minutes. 
A BRV responder is defined as a 
subject who achieves a reduction 
in seizure burden (ENS in minutes 
per hour), without need for rescue 
medication, compared to the 
seizure burden measured during 
the Baseline Period immediately 
prior to BRV administration, 
evaluated for a 2-hour period 
starting 1 hour after the start of 
initial BRV treatment. Reduction 
in seizure burden is defined as at 
least 80% reduction in nonsevere 
seizure burden (nonsevere seizure 
burden is defined as ≤50% seizure 
activity on VEEG in all 30-minute 
timespans) or at least 50% 
reduction in severe seizure burden 
(severe seizure burden is defined 
as >50% seizure activity on VEEG 
in any 30-minute timespan). 
Timespans of 30 minutes refer to 
the following intervals within the 
2-hour period: 0 to ≤30 minutes, 
>30 to ≤60 minutes, >60 to ≤90 
minutes, and >90 to ≤120 minutes. 
Clarification 
Section 1 
Summary 
Key efficacy variables 
Secondary efficacy variables 
Changed key efficacy variables to efficacy 
variables 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 2.1 
Epidemology 
and treatment 
of targeted 
disease 
Minor editorial changes 
Accepted 
Not applicable 
Section 2.2 
Background 
information 
regarding 
product 
Removed outdated background 
information 
Updated with new background 
information 
To provide more current marketing 
information 
Section 2.2 
Background 
information 
regarding 
product 
The following text was removed: 
The study was amended to allow 
direct enrollment of at least 100 
subjects 4 years to <17 years of 
age who have focal epilepsy. 
Subject participation in N01266 
will extend from study entry for 
approximately 3 years. 
No additional text was added 
Removed study information for N01266  
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Page 181 of 254 
Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 2.3 
Rationale for 
the study  
N01349 represents the first study 
of BRV in neonatal subjects, and 
will evaluate the PK, efficacy, 
and safety of BRV in neonates 
(with an age of 34 weeks to less 
than 42 weeks of GA at birth and 
up to 28 days of postnatal age at 
the time of enrollment) with 
repeated EEG seizures. A 
historical control group treated 
with MDZ from literature 
(matched in age and condition) 
will be used for the evaluation of 
efficacy. 
 
N01349 represents the first study 
of BRV in neonatal subjects, and 
will evaluate the PK, efficacy, and 
safety of BRV in neonates (up to 
27 days of PNA and preterm 
neonates up to 40 weeks of PMA 
and 27 days of PNA. 
 
Age at enrollment was modified 
Section 3.1 
Primary 
objective 
and Section 
3.2 
Secondary 
objectives 
Removed “PB” 
Added “previous AED” 
PB no longer required as first line treatment 
prior to BRV 
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Page 182 of 254 
Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 4.1 
PK variables 
(Exploratory 
and 
Confirmatory 
Cohorts) 
The PK variables, all of which are 
primary, are as follows: 
• Plasma concentrations of 
BRV and its metabolites 
ucb-42145 (acid), ucb-
100406-1 (hydroxy), and 
ucb-107092-1 
(hydroxyacid) 
• AUC, volume of 
distribution, and clearance 
of BRV 
• Plasma concentrations of 
concomitant AEDs (PB 
and PHT)  
•  
Section 4.1.1 Primary PK variable 
The primary PK variable is as 
follows: 
• Plasma concentrations of 
BRV following first dose 
on Day 1 
Section 4.1.2 Other PK variables 
• Plasma concentrations of BRV 
on other occasions 
• Plasma concentrations of BRV 
metabolites ucb-42145 (acid), 
ucb-100406-1 (hydroxy), and 
ucb-107092-1 (hydroxyacid) 
• AUC, volume of distribution, 
and clearance of BRV 
• Plasma concentrations of 
concomitant AEDs if 
administered  
PK variables were split into “Primary and 
Other PK variables” 
Section 4.2.1  Title: Key efficacy variables 
Title: Secondary efficacy variables Clarification throughout Section 4.2.1 
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Page 183 of 254 
Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 4.2.1 
Secondary 
efficacy 
variables 
A BRV responder is defined as a 
subject who achieves the 
following reduction in seizure 
burden (ENS in minutes per hour) 
compared to the seizure burden 
measured during the 2-hour 
Baseline Period immediately 
prior to BRV administration, 
evaluated for a 2-hour period 
starting 1 hour after the start of 
initial BRV treatment: 
− At least 80% reduction in 
nonsevere seizure burden 
(Nonsevere seizure burden 
is defined as ≤50% seizure 
activity on VEEG in any 
30-minute timespan) 
• A BRV responder is defined as 
a subject who achieves the 
following reduction in seizure 
burden (ENS in minutes per 
hour) without need for rescue 
medication, compared to the 
seizure burden measured 
during the Baseline Period 
immediately prior to BRV 
administration, evaluated for a 
2-hour period starting 1 hour 
after the start of initial BRV 
treatment: 
− At least 80% reduction in 
nonsevere seizure burden 
(Nonsevere seizure burden 
is defined as ≤50% seizure 
activity on VEEG in all 
30-minute timespans) 
Updated the definition of a BRV responder 
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Page 184 of 254 
Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 4.2.1 
Secondary 
efficacy 
variables 
For this study, an ENS is defined 
as an EEG seizure lasting for at 
least 10 seconds on VEEG. 
Baseline seizure burden is defined 
as seizure burden measured on 
the continuous VEEG (total ENS 
in minutes per hour) during a 
period of 2 hours immediately 
prior to the first administration of 
study drug. 
For this study, an ENS is defined 
as an EEG seizure lasting for at 
least 10 seconds on VEEG. 
Baseline seizure burden is defined 
as seizure burden measured on the 
continuous VEEG (total ENS in 
minutes per hour) during a period 
of up to 1 hour immediately prior 
to the first administration of study 
drug. 
For this study, updated the ENS definition  
Section 4.2.1 
Secondary 
efficacy 
variables 
• Absolute and percentage 
reduction in average seizure 
burden measured by 
continuous VEEG from 
Baseline to the end of the 
96-hour Evaluation Period 
• Proportion of BRV 
responders during the 96-hour 
Evaluation Period (measured 
at the end of the 96-hour 
Evaluation Period) 
• Absolute reduction in average 
seizure burden measured by 
continuous VEEG from 
Baseline to the end of the 
96-hour Evaluation Period 
• Percent reduction in average 
seizure burden measured by 
continuous VEEG from 
Baseline to the end of the 96-
hour Evaluation Period 
• Proportion of BRV responders 
at the end of the 96-hour 
Evaluation Period  
“Absolute and percentage reduction in 
average seizure burden” were given 
2 separate bullet points. Clarified that the 
proportion of BRV responders “at the end 
of the 96-hour Evaluation Period”. 
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Page 185 of 254 
Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 4.2.1 
Secondary 
efficacy 
variables 
• Proportion of subjects who 
are seizure-free by time 
interval at 3 hours, at 3-hour 
intervals thereafter through 24 
hours, and every 12 hours to 
24 hours following the start of 
the initial BRV treatment 
• Absolute and percent 
difference in clinical seizures 
at the end of the 24-hour 
Evaluation Period from 
Baseline for neonates with 
motor seizures at the time of 
inclusion 
 
• Proportion of subjects who are 
seizure-free by time interval at 
3 hours, at 3-hour intervals 
thereafter through 24 hours, 
and every 12 hours to 24 hours 
thereafter up until the end of 
the 96-hour evaluation period 
following the start of the initial 
BRV treatment 
• Absolute difference in clinical 
seizures at the end of the 24-
hour Evaluation Period from 
Baseline for neonates with 
motor seizures at the time of 
inclusion 
• Percent difference in clinical 
seizures at the end of the 24-
hour Evaluation Period from 
Baseline for neonates with 
motor seizures at the time of 
inclusion 
Timepoint clarifications and “absolute and 
percent difference in clinical seizures“ were 
given 2 separate bullet points  
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Page 186 of 254 
Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 4.2.2 
Other 
efficacy 
variables 
• Absolute and percentage 
reduction from Baseline in 
seizure burden at evaluation 
periods of 0 hours to 3 hours, 
>3 hours to 6 hours, >6 hours 
to 12 hours, >12 hours to 
24 hours, >24 hours to 36 
hours, >36 hours to 48 hours, 
>48 hours to 72 hours, and 
>72 hours to 96 hours after 
the start of initial BRV 
treatment 
 
• Absolute reduction from 
Baseline in seizure burden at 
evaluation periods of 0 hours 
to 3 hours, >3 hours to 6 hours, 
>6 hours to 12 hours, 
>12 hours to 24 hours, 
>24 hours to 36 hours, 
>36 hours to 48 hours, 
>48 hours to 72 hours, and 
>72 hours to 96 hours after the 
start of initial BRV treatment 
• Percent reduction from 
Baseline in seizure burden at 
evaluation periods of 0 hours 
to 3 hours, >3 hours to 6 hours, 
>6 hours to 12 hours, 
>12 hours to 24 hours, 
>24 hours to 36 hours, 
>36 hours to 48 hours, 
>48 hours to 72 hours, and 
>72 hours to 96 hours after the 
start of initial BRV treatment 
“Absolute and percentage reduction from 
Baseline in seizure burden” were given 
2 separate bullet points. 
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Page 187 of 254 
Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 4.3 
Safety 
variables 
(Exploratory 
and 
Confirmatory 
Cohorts) 
The safety variables are as 
follows: 
• AEs as reported by the 
Investigator  
• Change from Baseline in 
EEG-parameters 
(assessment of sedation) 
to the end of the 
Evaluation Period  
Section 4.3.1 Secondary safety 
variable 
The secondary safety variable is as 
follows: 
• AEs as reported by the 
Investigator 
Section 4.3.2 Other safety 
variables  
• Change from Baseline in 
EEG-parameters 
(assessment of sedation) to 
the end of the Evaluation 
Period (Confirmatory 
Cohorts only) 
Separated safety variables into “Secondary” 
and “Other”  
 
 
 
 
 
 
 
Clarification 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 5.1 
Study 
description 
N01349 consists of 2 steps 
including a comparison with a 
historical control from literature 
(MDZ treatment from literature 
of subjects matched in age and 
condition) for the evaluation of 
efficacy. 
For the Exploratory Cohort (first 
step), enrolled subjects will 
receive one or multiple 
therapeutic doses or continuous 
infusion of MDZ (dose and 
dosing frequency of MDZ are at 
the discretion of the Investigator) 
prior to receiving BRV. 
N01349 consists of 2 steps 
including a comparison with a 
historical control group (matched 
in age and condition) treated with 
AEDs comparable SOC and 
diagnostic methods from literature 
will be used for the evaluation of 
efficacy. 
For the Exploratory Cohort (first 
step), enrolled subjects will 
receive one or more AEDs for the 
treatment of ENS per SOC (first-
line, second-line, or subsequent 
treatment; choice of treatment, 
dose, and dosing frequency are at 
the discretion of the Investigator) 
prior to receiving BRV. 
Historical control changed from “MDZ” to 
“one or more AED treatments”  
 
Section 5.1 
Study 
description 
Removed reference to N01266 
Not applicable 
Reference to N01266 removed since this 
study will be closed before the last N01349 
subject was able to participate in that study 
for 3 years. 
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Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 5.1 
Study 
description 
Interpretation of the VEEGs will 
be done by local readers but may 
be supported by the blinded 
central reader, as needed. 
Subjects will be evaluated with 
VEEG monitoring at least during 
the Baseline, Evaluation, and 
Down-Titration (Confirmatory 
Cohorts only) Periods. 
Interpretation of VEEGs recorded 
for the Confirmatory Cohorts will 
be done by local readers but may 
be supported by the blinded 
central reader, as needed. 
Subjects assigned to the 
Confirmatory Cohorts will be 
evaluated with VEEG monitoring 
at least during the Baseline, 
Evaluation, and Down-Titration 
Period. 
Clarification 
Section 5.1 
Study 
description 
However, every effort should be 
made to avoid VEEG interruption 
of the 2-hour Baseline VEEG and 
during the first 3 hours after the 
start of the initial BRV 
administration for the 
Confirmatory Cohort. 
However, every effort should be 
made to avoid VEEG interruption 
of the Baseline VEEG and during 
the first 3 hours after the start of 
the initial BRV administration. 
Clarification 
Section 5.1 
Study 
description 
The schedule of assessments 
during the BRV Extension, 
Down-Titration, and Safety 
Follow-Up Periods for both the 
Exploratory and Confirmatory 
Cohorts are presented in 
Table 5-3 
The schedule of assessments 
during the BRV Extension, Down-
Titration (Confirmatory Cohorts 
only), and Safety Follow-Up 
Periods for both the Exploratory 
and Confirmatory Cohorts are 
presented in Table 5-3. 
Clarification 
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Page 190 of 254 
Section 
Impacted 
Key components of previous text 
Key components of amended text 
Rationale 
Section 5.1.1 
Exploratory 
Cohort 
For the Exploratory Cohort, at 
least 6 subjects who do not have 
adequate seizure control after 
receiving 1 to 3 doses of PB (PB 
treatment may have started prior 
to the subject’s admission into the 
study site; total therapeutic 
administered dose of 20 to 
40mg/kg; dosing regimen at the 
Investigator’s discretion) will be 
enrolled and dosed with one or 
multiple therapeutic doses of 
MDZ (dose and dosing frequency 
of MDZ are at the discretion of 
the Investigator). Phenobarbital 
treatment must be discontinued 
prior to entering the Evaluation 
Period. 
Approximately 3 hours after the 
initiation of MDZ dosing, an 
initial low dose of BRV 
(0.5mg/kg [bid]) will be 
administered according to the 
standard of care. Treatment with 
MDZ will continue in parallel 
with BRV treatment. After the 
Exploratory Cohort completes the 
study, a PK and safety data 
review will be performed by the 
For the Exploratory Cohort, at 
least 6 subjects who do not have 
adequate seizure control after they 
received one or more AEDs per 
SOC for the treatment of ENS 
(first-line, second-line, or 
subsequent treatment, which may 
have started prior to the subject’s 
admission into the study site; 
choice of treatment, dose, and 
dosing regimen at the 
Investigator’s discretion) will be 
enrolled. The AED treatment per 
SOC can be continued when BRV 
dosing is initiated. Alternatively, 
another AED treatment (choice of 
treatment, dose, and dosing 
regimen at the Investigator´s 
discretion) must be initiated and 
continue in parallel with BRV 
treatment. 
At any time after AED treatment 
per SOC for the treatment of ENS 
(first-line, second-line, or 
subsequent treatment) was 
initiated, an initial low dose of 
BRV (0.5mg/kg [bid]) will be 
administered at the Investigator´s 
discretion. After the Exploratory 
Cohort completes the study, a PK 
PB no longer required as first line treatment 
prior to BRV. Historical control changed 
from “MDZ” to “one or more AED 
treatments”. Clarification that enrollment 
will be put on hold during the first DMC 
 
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Data Monitoring Committee 
(DMC). 
and safety data review will be 
performed by the DMC. During 
the review of data from the 
Exploratory Cohort, the 
enrollment of subjects will be on 
hold. 
Section 5.1.1 
Exploratory 
Cohort 
• Screening Period: from 
signing and dating of the 
written Informed Consent 
form (ICF) up to Cohort 
Assignment. 
• Screening Period: from signing 
and dating of the written ICF 
up to initiation of the first 
BRV dose. 
For consistency, “Cohort Assignment” 
changed globally to “up to initiation of the 
first BRV dose”. 
Section 5.1.1 
Exploratory 
Cohort 
The Screening Period is up to 36 
hours prior to the first 
administration of MDZ 
(depending on the number of PB 
doses and time between PB doses 
and the interval between PB 
treatment and first administration 
of MDZ). The PB treatment may 
have been administered prior to 
the subject’s enrollment in the 
study and/or at a location other 
than the study site. 
− Baseline Period (included 
in the Screening Period): 
2 hours immediately prior 
to the start of MDZ 
infusion. The occurrence 
The Screening Period starts up to 
36 hours prior to the first 
administration of BRV. 
Phenobarbital, MDZ, PHT, LEV, 
or LDC may have been 
administered prior to the subject’s 
enrollment into the study and/or at 
a location other than the study site. 
Subjects will enter the Evaluation 
Period and start BRV treatment as 
soon as the occurrence of ENS per 
inclusion criterion 2a is confirmed 
by the Investigator based on local 
EEG. 
Two-hour Baseline EEG and 48-hour 
VEEG removed from the Exploratory 
Cohort; required ENS to be confirmed by 
the Investigator via local EEG 
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of ENS during the 2-hour 
Baseline Period must be 
confirmed either by the 
local or central VEEG 
reader prior to drug 
administration. Preferably, 
the central VEEG reader 
should confirm the 
required ENS. Video-
EEGs that are acquired 
per standard of care prior 
to consenting and meet 
study-specific technical 
and quality requirements 
(eg, ability for immediate 
cloud-based central 
review) can be used as 
part of the Baseline 
assessment VEEG.  
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Section 5.1.1 
Exploratory 
Cohort 
• Evaluation Period (in 
total, 51 hours: 3 hours for 
the evaluation of MDZ 
and 48 hours for the 
evaluation of BRV): The 
first MDZ infusion marks 
the starting point of the 
Evaluation Period. 
Subjects will receive iv 
MDZ (one or multiple 
therapeutic doses or 
continuous infusion; MDZ 
dose and dosing frequency 
are at the discretion of the 
Investigator). Three hours 
after the initial dose of 
MDZ, a low dose of BRV 
(0.5mg/kg) will be 
administered as an 
approximately 15-minute 
iv infusion; additional 3 
doses of BRV(0.5mg/kg) 
can be administered every 
12 hours for 48 hours (at 
the discretion of the 
Investigator). 
• Evaluation Period 
(48 hours): The first BRV 
infusion marks the starting 
point of the Evaluation 
Period. At any time after 
AED treatment per SOC 
for the treatment of ENS 
(first-line, second-line, or 
subsequent treatment) was 
initiated, a low dose of 
BRV (0.5mg/kg) will be 
administered as an 
approximately 15-minute 
iv infusion; additional 
3 doses of BRV(0.5mg/kg) 
can be administered every 
12 hours for 48 hours (at 
the discretion of the 
Investigator). The AED 
treatment per SOC can be 
continued when BRV 
dosing is initiated. 
Otherwise, another AED 
treatment (choice of 
treatment, dose, and dosing 
regimen at the 
Investigator´s discretion) 
must be initiated and 
continue in parallel with 
BRV treatment. 
Treatment with “MDZ only” during the 
first 3 hours of the Evaluation Period 
removed from the Confirmatory Cohort; 
duration of the Evaluation Period hence 
shortened from 51 to 48 hour. Historical 
control changed from “MDZ” to “one or 
more AED treatments”. Other updates for 
clarification purposes. 
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Section 5.1.2 
Confirmatory 
Cohorts 
A total of at least 36 subjects 
without adequate seizure control 
after receiving 1 to 3 doses of PB 
(PB treatment may have started 
prior to the subject’s admission 
into the study site; total 
therapeutic administered dose of 
20 to 40mg/kg; dosing regimen at 
the Investigator’s discretion) will 
enter the Confirmatory Cohorts. 
Phenobarbital treatment must be 
discontinued prior to entering the 
Evaluation Period. 
A total of at least 36 subjects 
without adequate seizure control 
after receiving one or more of the 
following AEDs prior to or at the 
time of enrollment: PB, MDZ, 
PHT, LEV (≤60mg/kg/day), or 
LDC (first-line, second-line, or 
subsequent treatment, which may 
have started prior to the subject’s 
admission into the study site; dose 
and dosing regimen at the 
Investigator’s discretion) will 
enter the Confirmatory Cohorts. 
The AED treatment can be 
continued if the subject is on a 
stable dose for at least 1 hour at 
the time the first BRV infusion is 
initiated. 
Phenobarbital no longer required as first 
line treatment prior to BRV; replaced by 
“one or more of the following AEDs: PB, 
MDZ, PHT, LEV (≤60mg/kg/day) or LDC 
(first-line, second-line or subsequent 
treatment; dose and dosing at the 
Investigator´s discretion)” for the 
Confirmatory Cohorts. Other edits for 
clarification purposes. 
Section 5.1.2 
Confirmatory 
Cohorts 
Screening Period: from signing 
and dating of the written ICF up 
to Cohort Assignment. 
• The Screening Period is up to 
36 hours prior to the first 
administration of BRV 
(depending on the number of 
PB doses and time between PB 
doses and the interval between 
PB treatment and first 
administration of BRV). The 
Screening Period: from signing 
and dating of the written ICF up to 
initiation of the first BRV dose. 
• The Screening Period starts up 
to 36 hours prior to the first 
administration of BRV. 
Phenobarbital, MDZ, PHT, LEV 
(≤ 60mg/kg/day), or LDC may 
have been administered prior to 
the subject’s enrollment into the 
Clarified to define Baseline Period as part 
of Screening Period. Definition of status 
epilepticus for neonates enrolled into this 
study was added 
 
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PB treatment may have been 
administered prior to the 
subject’s enrollment in the 
study and/or at a location other 
than the study site. 
• Baseline Period (included 
in the Screening Period): 
2 hours immediately prior 
to the start of BRV 
infusion. The occurrence 
of ENS during the 2-hour 
Baseline Period must be 
confirmed either by the 
local or central VEEG 
reader prior to drug 
administration. 
study and/or at a location other 
than the study site. 
◦ 
Baseline Period (included in 
the Screening Period):  
o For subjects with 
intermittent ENS: at least 
1 hour prior to entering the 
Evaluation Period  
o For subjects in status 
epilepticus: up to 30 
minutes prior to entering 
the Evaluation Period. At 
least 15 minutes of 
continuous seizures, or 
50% of cumulative seizure 
activity during a 30-minute 
interval are to be 
confirmed on EEG before 
the administration of BRV 
can start. 
As soon as subjects are 
considered to be in status 
epilepticus, steps required 
for the preparation of the 
initial BRV infusion can be 
initiated (eg, assignment of 
BRV kits through 
interactive response 
technology [IRT] and the 
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dilution of BRV solution 
for iv infusion), even if the 
required EEG recording is 
not completed by that time.  
• Status epilepticus in 
neonates for the purpose of 
this study is defined as 
follows: 
o 15 minutes of 
continuous or 
cumulative 
electrographic or 
electroclinical 
seizure within 30 
minutes 
The occurrence of ENS during the 
Baseline Period must be 
confirmed either by the local or 
central VEEG reader prior to BRV 
administration. 
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Section 5.1.3 
Study 
duration per 
subject 
The maximum study duration per 
subject will be up to 75 days 
(Screening Period, Baseline 
Period, Evaluation Period, BRV 
Extension Period, Down-Titration 
Period, and Safety Follow-Up 
Period). The individual study 
duration will be shorter 
depending on the type of cohort 
to which subjects will be 
assigned, the age at enrollment, 
and the decision to enter into the 
BRV Extension Period. 
The maximum study duration per 
subject will be up to 75 days 
(Screening Period [including 
Baseline Period (Confirmatory 
Cohorts only)], Evaluation Period, 
BRV Extension Period, 
Down-Titration Period 
[Confirmatory Cohorts only], and 
Safety Follow-Up Period). The 
individual study duration will be 
shorter depending on the type of 
cohort to which subjects will be 
assigned, the age at enrollment, 
and the decision to enter the BRV 
Extension Period. 
Clarification 
Table 5-1 
Schedule of 
assessments - 
Screening 
and 
Evaluation 
Periods 
(Exploratory 
Cohort) 
Column heading 2: 
-36h to -2h 
Column Heading 3: 
Baseline Period 
MDZ 
-2h to 0h 
Column heading 2: 
-36h to 0h 
Column heading 3: 
Timepoint immediately before first 
BRV administration 
Updated to reflect changes throughout 
protocol 
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Table 5-1 
Schedule of 
assessments - 
Screening 
and 
Evaluation 
Periods 
(Exploratory 
Cohort) 
Not applicable 
Time point immediately before 
first BRV administration: 
Vital signs  
Physical and neurological 
examination Sarnat scale for 
subjects with HIE 
Body weight 
Added the following to -36h to 0h: 
Primary cause of seizure 
Psychometric parameters: N-PASS 
and EEG-parameters 
Updates based on updates made throughout 
the protocol 
Table 5-1 
Schedule of 
assessments - 
Screening 
and 
Evaluation 
Periods 
(Exploratory 
Cohort) 
PB infusion 
VEEG-removed 
AEDs-removed 
AED PK sample 
AED treatment per SOC 
 
 
AED PK sample (only when PB 
and PTH are used) 
Change as reflected throughout protocol 
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Table 5-1 
Schedule of 
assessments - 
Screening 
and 
Evaluation 
Periods 
(Exploratory 
Cohort) 
Footnote a 
Screening Period is from signing 
and dating of the written ICF up 
to Cohort Assignment. 
Footnote c 
The occurrence of ENS during 
the 2-hour Baseline Period must 
be confirmed either by the local 
or central VEEG reader prior to 
drug administration. Preferably, 
the central VEEG reader should 
confirm the required ENS. 
Footnote d 
Measurement of body weight is 
optional at 24 and 48 hours. 
Dosage of BRV during the 
Evaluation Period will be based 
on the subject’s weight measured 
prior to the start of the first BRV 
administration. However, dosage 
calculation can be adjusted to a 
more recent weight measurement, 
upon discretion of the 
Investigator, if weight is 
measured during the Evaluation 
Period. 
Footnote a 
Screening Period is from signing 
and dating of the written ICF up to 
initiation of the first BRV dose. 
Footnote c 
The occurrence of ENS prior to 
entering the Evaluation Period 
must be confirmed by the local 
VEEG reader prior to initial BRV 
administration.  
 
 
Footnote d 
Measurement of body weight is 
mandatory prior to BRV treatment 
and optional at 24 and 48 hours. 
Dosage of BRV during the 
Evaluation Period will be based on 
the subject’s weight measured 
prior to the start of the first BRV 
administration. However, dosage 
calculation can be adjusted to a 
more recent weight measurement, 
upon discretion of the Investigator, 
if weight is measured during the 
Evaluation Period. 
Change as reflected throughout protocol 
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Table 5-2 
Schedule of 
assessments - 
Screening and 
Evaluation 
Periods 
(Confirmatory 
Cohorts) 
Column 2: 
-36h to -2h 
Column 3: 
-2h to 0h 
Column 2: 
-36h to up to -1h 
Column 3: 
Up to -1h to 0h 
Change as reflected throughout protocol 
Table 5-2 
Schedule of 
assessments - 
Screening and 
Evaluation 
Periods 
(Confirmatory 
Cohorts) 
PB infusion 
 
 
 
 
 
 
AED PK sample 
AED treatment (PB, MDZ, PHT, 
LEV [≤60mg/kg/day], or LDC)n 
Assessment to be completed 
during the Screening Period (both 
visits) and at all timepoints after 
6h during the Evaluation Period  
 
AED PK sample (only when PB 
and PHT are used) 
Change as reflected throughout protocol 
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Table 5-2 
Schedule of 
assessments - 
Screening and 
Evaluation 
Periods 
(Confirmatory 
Cohorts) 
Footnote a: 
Screening Period is from signing 
and dating of the written ICF up 
to Cohort Assignment. 
 
Not applicable 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Footnote d: 
The occurrence of ENS during 
the 2-hour Baseline Period must 
be confirmed either by the local 
or central VEEG reader prior to 
drug administration. Preferably, 
the central VEEG reader should 
confirm the required ENS. 
Footnote a: 
Screening Period is from signing 
and dating of the written ICF up to 
initiation of the first BRV dose. 
 
Footnote b added: 
The duration of the Baseline EEG 
depends on seizure activity. 
Subjects with intermittent seizures 
will enter the Evaluation Period 
based on at least 1 hour of EEG 
recording. Subjects in status 
epilepticus will enter the 
Evaluation Period based on up to 
30 minutes of EEG recording, ie, 
as soon as 15 minutes of 
continuous seizures or 50% of 
cumulative seizure activity is 
confirmed on EEG. 
 
Subsequent footnotes were 
re-alphabetized. 
  
Footnote e: 
The occurrence of ENS during the 
Baseline Period must be confirmed 
either by the local or central 
VEEG reader prior to drug 
administration. Preferably, the 
central VEEG reader should 
confirm the required ENS. 
Change as reflected throughout protocol 
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Section 5.3 
Schematic 
diagrams 
Figure 5-1, Figure 5-2, Figure 5-
3, and Figure 5-4 
Figure 5-1, Figure 5-2, Figure 5-3, 
and Figure 5-4 
All figures updated to reflect protocol 
changes 
Section 5.4.1 
Rationale for 
study design 
Thus, study N01349 was 
designed to include PB as the first 
line of treatment, and only those 
subjects who do not have 
adequate seizure control with PB 
will be permitted to continue in 
the study 
Thus, study N01349 was designed 
for a flexible treatment of ENS, 
and only those subjects who do not 
have adequate seizure control with 
previous AED treatment will be 
permitted to continue in the study 
PB no longer required as first line treatment 
prior to BRV 
Section 5.4.1 
Rationale for 
the study 
design  
Thus, only neonates with an age 
at birth of 34 weeks to less than 
42 weeks of GA (and up to 
28 days of postnatal age at the 
time of enrollment) with repeated 
neonatal seizures (assessed by 
VEEG) will be enrolled in 
N01349. 
At enrollment, subjects must be at 
least 34 weeks of CGA. In 
addition, term neonates up to 
27 days of PNA and preterm 
neonates up to 40 weeks of PMA 
and 27 days of PNA can be 
enrolled. 
Age at enrollment has been modified 
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Section 6.1 
Inclusion 
Criteria 
2a. Confirmation on VEEG of 
≥2 minutes of cumulative ENS or 
≥3 identifiable ENS within the 
2 hours prior to entering the 
Evaluation Period (ENS is 
defined as a seizure lasting for at 
least 10 seconds on VEEG), 
despite receiving PB (total 
therapeutic administered dose of 
20 to 40mg/kg) for the treatment 
of repeated seizures. 
 
The occurrence of ENS during 
the 2-hour period must be 
confirmed either by the local or 
central VEEG reader prior to drug 
administration. Preferably, the 
central VEEG reader should 
confirm the required ENS. 
2a. Confirmation on VEEG of 
≥2 minutes of cumulative ENS or 
≥3 identifiable ENS prior to 
entering the Evaluation Period 
(ENS is defined as a seizure 
lasting for at least 10 seconds on 
VEEG), despite receiving previous 
AED treatment for the treatment of 
electroencephalographic seizures. 
 
 
 
The occurrence of ENS during an 
up to 1-hour period must be 
confirmed either by the local or 
central VEEG reader prior to drug 
administration. Preferably, the 
central VEEG reader should 
confirm the required ENS 
Based on agency recommendation, the 
2-hour Baseline EEG has been removed.  
 
 
 
 
 
 
 
For clarification 2-hour period was replaced 
with up to 1-hour period 
Section 6.1 
Inclusion 
Criteria 
3. Subject is male or female, with 
an age at birth of 34 weeks to less 
than 42 weeks of GA and up to 
28 days of postnatal age at the 
time of enrollment. 
3. Subject is male or female and 
must be at least 34 weeks of CGA. 
In addition, term neonates up to 
27 days of PNA and preterm 
neonates up to 40 weeks of PMA 
and 27 days of PNA can be 
enrolled 
Based on feedback from Investigators, the 
age of subjects allowed to participate in the 
study will be extended to help with 
enrollment. 
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Section 6.2 
Exclusion 
Criteria 
1a. Subject received AED 
treatment (other than the required 
1 to 3 doses of PB [total 
therapeutic administered dose of 
20 to 40mg/kg] for the treatment 
of repeated seizures) prior to 
entering the Evaluation Period. 
1a. Subject receiving AED 
treatment other than PB, MDZ, 
PHT, LEV (≤60mg/kg/day), or 
LDC for the treatment of seizures 
prior to or at the time of 
enrollment (Confirmatory Cohorts 
only). 
Phenobarbital no longer required as first 
line treatment prior to BRV 
Section 6.2 
Exclusion 
Criteria 
2. Subject with seizures 
responding to PB (total 
therapeutic administered dose of 
20 to 40mg/kg), pyridoxine 
treatment, or correction of 
metabolic disturbances 
(hypoglycemia, hypomagnesemia 
or hypocalcemia). 
2. Subject with seizures 
responding to previous AED 
treatment immediately prior to 
BRV treatment, pyridoxine 
treatment, or correction of 
metabolic disturbances 
(hypoglycemia, hypomagnesemia, 
or hypocalcemia). 
Phenobarbital no longer required as first 
line treatment prior to BRV 
Section 7.1 
Description of 
investigational
medicinal 
products 
Refer to the pharmacy manual for 
further details on the handling of 
BRV. 
 
Refer to the IMP Handling Manual 
for further details on the handling 
of BRV. 
 
Clarification 
Section 7.1 
Description of 
investigational
medicinal 
products 
Not applicable 
After the completion of the study, 
BRV treatment per SOC may be 
continued as prescribed but will 
not be provided by the Sponsor. 
Clarification 
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Section 7.2 
Treatments to 
be 
administered 
Subjects in the Exploratory 
Cohort will be dosed with iv 
MDZ (dosing and dosing 
frequency of MDZ are at the 
discretion of the Investigator). 
Three hours after the start of 
MDZ infusion, BRV dosing 
(0.5mg/kg bid) will start 
according to the standard of care. 
Treatment with MDZ will 
continue in parallel with BRV 
treatment. 
Subjects in the Exploratory Cohort 
will be dosed with BRV (0.5mg/kg 
bid) according to the sites standard 
procedures. Treatment with AEDs 
per SOC (first-line, second-line, or 
subsequent treatment) will 
continue in parallel with BRV 
treatment. 
Historical control changed from “MDZ”. 
Section 7.2 
Treatments to 
be 
administered 
Not applicable 
Treatment with previous AEDs 
(PB, MDZ, PHT, LEV 
[≤60mg/kg/day], or LDC) is 
permitted to continue if the subject 
is on a stable dose from 1 hour 
prior to initiation of the BRV 
treatment. 
Clarification 
Section 7.3 
Packaging 
Commercial MDZ will be used 
for this study and will not be 
provided by the Sponsor. 
Other AED treatments will be used 
for this study and will not be 
provided or covered by the 
Sponsor. 
 
Historical control changed from “MDZ”. 
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Section 7.5 
Handling and 
storage 
requirements 
Appropriate storage conditions 
must be ensured either by 
controlling the temperature (eg, 
room, refrigeration unit) or by 
completing a temperature log in 
accordance with local 
requirements on a regular basis 
(eg, once a week), showing actual 
minimum/maximum temperatures 
reached over the time interval. 
 
Appropriate storage conditions 
must be ensured either by 
controlling the temperature (eg, 
room, refrigeration unit) or by 
completing a temperature log in 
accordance with local 
requirements on a regular basis 
(eg, once per working day), 
showing actual 
minimum/maximum temperatures 
reached over the time interval. 
 
Clarification 
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Section 7.8.1 
Permitted 
concomitant 
treatments 
(medications 
and therapies) 
Concomitant treatment with 
AEDs is permitted as follows: 
Prior to first BRV 
administration: 
• PB 
• MDZ (Exploratory Cohort 
only) 
After first BRV administration: 
• Any AEDs (including MDZ) 
− Exploratory Cohort: from 
first BRV administration  
• Confirmatory Cohorts: from 
3 hours following first BRV 
administration 
For the Exploratory Cohort, 
concomitant treatment with AEDs 
is permitted at any time. 
For the Confirmatory Cohorts, 
concomitant treatment with AEDs 
is permitted to continue in parallel 
with BRV treatment if subjects are 
on a stable dose from 1 hour prior 
to initiation of BRV treatment. 
Changes to concomitant AEDs are 
permitted from 3 hours onward 
following first BRV 
administration. 
PB is no longer required as first-line 
treatment prior to BRV; historical control 
changed from MDZ. 
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Section 7.8.2 
Prohibited 
concomitant 
treatments 
(medications 
and therapies) 
For subjects treated with BZDs, at 
least 1 week should elapse before 
receiving the initial BRV dose. 
For the Exploratory Cohort, 
subjects will not be permitted to 
receive treatments for neonatal 
seizures (other than the specified 
PB doses and MDZ) prior to the 
first BRV administration. 
For the Confirmatory Cohorts, 
subjects will not be permitted to 
receive treatments for neonatal 
seizures (other than the specified 
PB doses) prior to and for the first 
3 hours after the first BRV 
administration.  
The use of LEV is prohibited 
throughout the study for both the 
Exploratory and Confirmatory 
Cohorts.   
For the Confirmatory Cohorts, 
subjects will not be permitted to 
change concomitant treatment for 
neonatal seizures for the first 
3 hours after the first BRV 
administration.  
The initiation of LEV treatment 
after the first time BRV is 
introduced is prohibited 
throughout the study for the 
Confirmatory Cohorts.   
Clarification 
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7.8.3 Rescue 
medication 
Rescue medication in this study is 
considered as any treatment with 
AEDs. Rescue medication can be 
given at any time if considered 
necessary by the Investigator.  
However, during the Evaluation 
Period rescue medication should 
not be administered – if possible 
– in the following time frames: 
• Prior to BRV dosing for the 
Exploratory Cohort (except 
for MDZ as scheduled in the 
Protocol). 
• During the first 3 hours after 
the initial dose of BRV for the 
Confirmatory Cohorts. If this 
occurs, subjects will be 
considered BRV 
nonresponders. 
 
Any treatment initiation with a 
new AED, or any increase of dose 
or frequency of an existing 
concomitant AED for the 
treatment of seizures during the 
Evaluation Period is considered 
rescue treatment. Rescue 
medication can be given at any 
time if considered necessary by the 
Investigator.  
However, during the Evaluation 
Period rescue medication should 
not be administered – if possible – 
in the following time frames: 
• During the first 3 hours after 
the initial dose of BRV for the 
Confirmatory Cohorts. If this 
occurs, subjects will be 
considered BRV 
nonresponders for the 
evaluation of the main efficacy 
variable. 
Clarification 
Section 8.1.1 
Screening 
Period 
The Screening Period will be 
from the signing and dating of the 
written ICF by the parent(s) or 
legal representative(s) of the 
subject to the end of the Baseline 
Period. Any AEs, AEDs, 
The Screening Period will be from 
the signing and dating of the 
written ICF by the parent(s) or 
legal representative(s) up to 
initiation of the first BRV dose. 
Any AEs, AEDs, concomitant 
Text has been updated to reflect the 
changes to the study schedule of 
assessments. Other text changes were also 
made to provide consistent language 
throughout the protocol. Section heading 
8.1.2 Baseline Period was deleted and text 
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concomitant medications, and 
medical procedures will be 
collected after the ICF is signed. 
The subject’s eligibility to 
participate in this study will be 
assessed. The subject 
identification card will be 
dispensed. 
The Screening Period is up to 36 
hours prior to the first 
administration of MDZ 
(depending on the number of PB 
doses and time between PB doses 
and the interval between PB 
treatment and first administration 
of MDZ). Body weight 
measurements can be taken 
between 36 hours and 2 hours for 
the determination of PB 
dosage (mg/kg). The PB 
treatment may have started prior 
to the subject’s admission to the 
study and/or at a location other 
than the study site but should be 
completed prior to the 2-hour 
Baseline Period.  
medications, and medical 
procedures will be collected after 
the ICF is signed. The subject’s 
eligibility to participate in this 
study will be assessed. The subject 
identification card will be 
dispensed. 
The Screening Period starts up to 
36 hours prior to the first 
administration of BRV. 
Phenobarbital, MDZ, PHT, LEV 
(≤ 60mg/kg/day), or LDC may 
have been administered prior to 
the subject’s enrollment into the 
study and/or at a location other 
than the study site. 
Subjects will enter the Evaluation 
Period and start BRV treatment as 
soon as the occurrence of ENS per 
inclusion criterion 2a is confirmed 
by the Investigator based on local 
EEG. 
The following assessments will be 
performed immediately before the 
first administration of BRV is 
initiated:  
• Verification of 
inclusion/exclusion criteria. 
Confirmation on VEEG of 
merged with Section 8.1.1. All subsequent 
section headings were updated. 
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At the determination of the 
Investigator, subjects achieving 
adequate seizure control after 
initial PB treatment (total 
therapeutic administered dose of 
20 to 40mg/kg; dosing regimen at 
the Investigator’s discretion) will 
be considered PB responders. 
Those subjects will be classified 
as screen failures and will not be 
assigned to BRV treatment 
≥2 minutes of cumulative ENS 
or ≥3 identifiable ENS prior to 
entering the Evaluation Period 
(ENS is defined as a seizure 
lasting for at least 10 seconds 
on VEEG), despite treatment 
with one or more AEDs per 
SOC  
• Vital signs (blood pressure, 
pulse rate, respiratory rate 
[including apneas], oxygen 
saturation [pulse oximetry], 
and body temperature) 
• Physical and neurological 
examination (Sarnat scale for 
subjects with HIE; physical 
examination will include a 
check for the presence of skin 
rash and skin hypersensitivity) 
• Body weight 
• Head circumference (to be 
taken within 7 days prior to 
drug administration, or at birth 
for subjects ≤7 days old)  
• Heart rate monitoring 
• Safety laboratory assessments 
(hematology, biochemistry, 
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liver enzymes, and 
endocrinology) 
• Thompson score (for subjects 
with HIE) 
• Mechanical ventilation 
• AEs as reported by the 
Investigator 
• Recording of AEDs, 
concomitant medications, and 
medical procedures 
Laboratory measurements will be 
performed by local laboratories 
unless historical data is available. 
Historical safety laboratory 
assessments, previously collected 
as standard of care, may be 
accepted from referring hospitals 
as measurement prior to first use 
of BRV if performed 36 hours 
prior to the start of the Evaluation 
Period. In this case, test results 
will be considered medical history. 
Prior laboratory assessment results 
should be available and verified 
prior to initiation of the first BRV 
infusion. 
At the determination of the 
Investigator, subjects achieving 
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adequate seizure control following 
AED treatment per SOC will be 
considered AED responders. 
Those subjects will be classified as 
screen failures and will not be 
assigned to BRV treatment. 
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Section 8.1.2  
Baseline 
Period 
The Baseline Period is included 
in the Screening Period; the 
period begins 2 hours before and 
ends at the initiation of the MDZ 
infusion. The occurrence of ENS 
during the 2-hour Baseline Period 
must be confirmed either by the 
local or central VEEG reader 
prior to drug administration. 
Preferably, the central VEEG 
reader should confirm the 
required ENS. Video-EEGs that 
are acquired per standard of care 
prior to consenting and meet 
study-specific technical and 
quality requirements (eg, ability 
for immediate cloud-based central 
review) can be used as part of the 
Baseline assessment VEEG.  
The following assessments will 
be performed during the Baseline 
Period:  
• Verification of 
inclusion/exclusion criteria. 
Confirmation on VEEG of 
≥2 minutes of cumulative 
ENS or ≥3 identifiable ENS 
within the 2 hours prior to 
entering the Evaluation Period 
(ENS is defined as a seizure 
lasting for at least 10 seconds 
Not applicable 
This section heading was deleted, and text 
merged into Section 8.1.1. Subsequent 
headings were renumbered 
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on VEEG), despite PB 
treatment prior to Baseline 
• Demographic data Medical 
history (including Apgar 
score) 
• Vital signs (blood pressure, 
pulse rate, respiratory rate, 
oxygen saturation [pulse 
oximetry] including apneas, 
and body temperature) 
• Physical and neurological 
examination (Sarnat scale for 
subjects with HIE; physical 
examination will include a 
check for the presence of skin 
rash and skin 
hypersensitivity) 
• Length  
• Body weight 
• Head circumference (Baseline 
measurement should be taken 
within 7 days prior to drug 
administration, or at birth for 
subjects ≤7 days old)  
• Primary cause of seizure 
(HIE, hemorrhage, or 
infarction; CNS 
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malformations; CNS 
infections; undetermined 
causes) 
• N-PASS and EEG parameters 
for the assessment of sedation 
• Video-EEG 
• Heart rate monitoring 
• Safety laboratory assessments 
(hematology, biochemistry, 
liver enzymes, and 
endocrinology) 
• Thompson score (for subjects 
with HIE) 
• Mechanical ventilation 
• AEs as reported by the 
Investigator 
Baseline laboratory 
measurements will be performed 
by local laboratories unless 
historical data is available. 
Historical safety laboratory 
assessments, previously collected 
as standard of care, may be 
accepted from referring hospitals 
as Baseline measurement if 
performed 36 hours prior to the 
start of the Evaluation Period. In 
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this case, test results will be 
considered medical history. Prior 
laboratory assessment results 
should already be available at 
Baseline and verified prior to 
initiation of the MDZ infusion. 
Section 8.1.4 
Evaluation 
Period 
The first MDZ infusion marks the 
starting point of the Evaluation 
Period. The Evaluation Period 
will last for 51 hours in total (3 
hours for the evaluation of MDZ 
and 48 hours for the evaluation of 
BRV). After the enrollment of 
subjects, the weight of the subject 
will be measured and MDZ will 
be administered.  
The following assessments will 
be performed at the start of and 3 
hours after the initial MDZ 
administration:  
• Vital signs (blood pressure, 
pulse rate, respiratory rate, 
oxygen saturation [pulse 
oximetry] including apneas, 
and body temperature); only 
at the start of MDZ 
administration 
• Video-EEG 
Section 8.1.3 Evaluation Period 
 
The first BRV infusion marks the 
starting point of the 48-hour 
Evaluation Period. 
An initial iv dose of BRV 
(0.5mg/kg) will be administered as 
an approximately 15-minute 
infusion. At the discretion of the 
Investigator, 3 additional iv BRV 
doses can be administered, up to a 
total of 4 iv BRV doses (0.5mg/kg 
bid) during the 48-hour BRV 
Evaluation Period.  
The following assessments will be 
performed after the end of the first 
BRV infusion:  
Text has been updated to reflect the 
changes to the study schedule of 
assessments. Other text changes were also 
made to provide consistent language 
throughout the protocol. 
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• Heart rate monitoring 
• AEs as reported by the 
Investigator 
• AEDs, concomitant 
medications, and medical 
procedures 
• Infusion site reaction 
monitoring 
Three hours post-start of initial 
MDZ infusion, an initial iv dose 
of BRV (0.5mg/kg) will be 
administered as an approximately 
15-minute infusion. At the 
discretion of the Investigator, 3 
additional iv BRV doses can be 
administered, up to a total of 4 iv 
BRV doses (0.5mg/kg bid) during 
the 48-hour BRV Evaluation 
Period.  
The following assessments will 
be performed after the first BRV 
administration:  
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Section 
8.1.4.2 
Extension 
Period Visit 2 
The EPV2 will be performed on 
the same day when the subject 
enters the long-term study. The 
following assessments will be 
performed: 
The EPV2 should be performed on 
the same day when the subject 
enters the long-term study. The 
following assessments will be 
performed: 
Clarification 
Section 8.2.1 
Screening 
Period 
The Screening Period will be 
from the signing and dating of the 
written ICF by the parent(s) or 
legal representative(s) of the 
subject to the end of the Baseline 
Period. Any AEs, AEDs, 
concomitant medications, and 
medical procedures will be 
collected after the ICF is signed. 
The subject’s eligibility to 
participate in this study will be 
assessed. The subject 
identification card will be 
dispensed. 
The Screening Period will be from 
the signing and dating of the 
written ICF by the parent(s) or 
legal representative(s) of the 
subject up to initiation of the first 
BRV dose. Any AEs, AEDs, 
concomitant medications, and 
medical procedures will be 
collected after the ICF is signed. 
The subject’s eligibility to 
participate in this study will be 
assessed. The subject 
identification card will be 
dispensed. 
The Screening Period starts up to 
36 hours prior to the first 
administration of BRV. The 
treatment with one or more of the 
following AEDs prior to or at the 
time of enrollment: PB, MDZ, 
PHT, LEV (≤60mg/kg/day), or 
LDC (first-line, second-line, or 
subsequent treatment; choice of 
treatment, dose, and dosing 
Text has been updated to reflect the 
changes to the study schedule of 
assessments. Other text changes were also 
made to provide consistent language 
throughout the protocol. 
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The Screening Period is up to 36 
hours prior to the first 
administration of BRV 
(depending on the number of PB 
doses and time between PB doses 
and the interval between PB 
treatment and first administration 
of BRV). Body weight 
measurements can be taken 
between 36 hours and 2 hours for 
the determination of PB 
dosage (mg/kg). The PB 
treatment may have started prior 
to the subject’s enrollment in the 
study and/or at a location other 
than the study site but should be 
completed prior to the 2-hour 
Baseline Period.  
At the determination of the 
Investigator, subjects achieving 
adequate seizure control after 
initial PB treatment (total 
therapeutic administered dose of 
20 to 40mg/kg; dosing regimen at 
the Investigator’s discretion) will 
be considered PB responders. 
regimen at the Investigator’s 
discretion) may have started prior 
to the subject’s enrollment in the 
study and/or at a location other 
than the study site.  
At the determination of the 
Investigator, subjects achieving 
adequate seizure control following 
any of the following AEDs: PB, 
MDZ, PHT, LEV (≤60mg/kg/day), 
or LDC will be considered AED 
responders. 
Section 8.2.2 
Baseline 
Period 
The Baseline Period will 
be2 hours immediately prior to 
the start of BRV infusion.  
Section 8.2.1.1 Baseline Period 
 
The Baseline Period will be up to 
Section heading numbering changed 
because Baseline is part of Screening. Text 
has been updated to reflect the changes to 
the study schedule of assessments. Other 
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The occurrence of ENS during 
the 2-hour Baseline Period must 
be confirmed either by the local 
or central VEEG reader prior to 
drug administration. 
1 hour immediately prior to the 
start of initial BRV infusion and 
depend on seizure activity:  
- For subjects with intermittent 
ENS: at least 1 hour prior to 
entering the Evaluation Period 
- For subjects in status epilepticus: 
up to 30 minutes prior to entering 
the Evaluation Period. At least 15 
minutes of continuous seizures, or 
50% of cumulative seizure activity 
during a 30-minute interval are to 
be confirmed on EEG before the 
administration of BRV can start. 
As soon as subjects are considered 
to be in status epilepticus, steps 
required for the preparation of the 
initial BRV infusion can be 
initiated (eg, assignment of BRV 
kits through interactive IRT and 
the dilution of BRV solution for iv 
infusion), even if the required 
EEG recording is not completed 
by that time. 
The occurrence of ENS during the 
Baseline Period must be confirmed 
either by the local or central 
VEEG reader prior to drug 
administration. 
text changes were also made to provide 
consistent language throughout the 
protocol. 
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• Verification of 
inclusion/exclusion criteria. 
Confirmation on VEEG of 
≥2 minutes of cumulative 
ENS or ≥3 identifiable ENS 
within the 2 hours prior to 
entering the Evaluation Period 
(ENS is defined as a seizure 
lasting for at least 10 seconds 
on VEEG), despite PB 
treatment prior to Baseline 
• Verification of 
inclusion/exclusion criteria. 
Confirmation on VEEG of 
≥2 minutes of cumulative ENS 
or ≥3 identifiable ENS within 
the 1 hour prior to entering the 
Evaluation Period (ENS is 
defined as a seizure lasting for 
at least 10 seconds on VEEG), 
despite treatment with one or 
more AEDs per SOC 
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Section 8.2.3 
Evaluation 
Period 
Not applicable  
The AED treatment initiated prior 
to first administration of BRV can 
be continued if the subject is on a 
stable dose for at least 1 hour at 
the time the first BRV infusion is 
initiated. 
Text has been updated to reflect the 
changes to the study schedule of 
assessments. Other text changes were also 
made to provide consistent language 
throughout the protocol. 
Section 8.2.4 
BRV 
Extension 
Period 
Extension Period Visit 2 will be 
performed on the same day when 
the subject enters the long-term 
study N01266 (see Section 
8.2.4.2). If study N01266 is 
performed outside the N01349 
hospital, an interval of up to 3 
days between the N01349 EPV2 
and N01266 Entry Visit is 
allowed. 
Extension Period Visit 2 will be 
performed on the same day when 
the subject enters the long-term 
study (see Section 8.2.4.2). If the 
long-term study is performed 
outside the N01349 hospital, an 
interval of up to 3 days between 
the N01349 EPV2 and long-term 
study Entry Visit is allowed. 
Text changes were made to provide 
consistent language throughout the 
protocol. 
Section 
8.2.4.2 
Extension 
Period Visit 2 
This visit will be performed on 
the same day when the subject 
enters the long-term study. 
This visit should be performed on 
the same day when the subject 
enters the long-term study. 
Text changes were made to provide 
consistent language throughout the 
protocol. 
Section 10.1  Title: Assessment of the key 
efficacy variables 
Title: Assessment of secondary 
efficacy variables (Confirmatory 
Cohort[s] only) 
Text changes were made to provide 
consistent language throughout the 
protocol. 
Section 10.1 
The main efficacy variable is: 
 
The main secondary efficacy 
variable is: 
 
Text changes were made to provide 
consistent language throughout the 
protocol. 
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A BRV responder is defined as a 
subject who achieved the 
following reduction in seizure 
burden (ENS in minutes per hour) 
compared to the seizure burden 
measured during the 2-hour 
Baseline Period immediately 
prior to BRV administration, 
evaluated for a 2-hour period 
starting 1 hour after the start of 
initial BRV treatment 
 
 
(Nonsevere seizure burden is 
defined as ≤50% seizure activity 
on VEEG in any 30-minute 
timespan) 
 
For this study, an ENS is defined 
as EEG seizure lasting for at least 
10 seconds on VEEG.  Baseline 
seizure burden is defined as 
seizure burden measured on the 
continuous VEEG (total ENS in 
minutes per hour) during a period 
of 2 hours immediately prior to 
the first administration of study 
drug. 
A BRV responder is defined as a 
subject who achieved the 
following reduction in seizure 
burden (ENS in minutes per hour) 
without need for rescue 
medication, compared to the 
seizure burden measured during 
the Baseline Period immediately 
prior to BRV administration, 
evaluated for a 2-hour period 
starting 1 hour after the start of 
initial BRV treatment 
 
(Nonsevere seizure burden is 
defined as ≤50% seizure activity 
on VEEG in all 30-minute 
timespans) 
 
For this study, an ENS is defined 
as EEG seizure lasting for at least 
10 seconds on VEEG.  Baseline 
seizure burden is defined as 
seizure burden measured on the 
continuous VEEG (total ENS in 
minutes per hour) during a period 
of up to 1 hour immediately prior 
to the first administration of study 
drug. 
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For the analysis of the main 
efficacy variable (Section 4.2.1), 
subjects that are switched to 
another AED or have been 
administered any rescue 
medication (including BZDs) 
during the first 3 hours after 
initiation of BRV treatment will 
be considered BRV 
nonresponders.  
Subjects must not have switched 
to another AED or used >1 dose 
of rescue medication (including 
BZDs) following the first 3 hours 
after initiation of BRV treatment 
to be considered BRV responders 
for the analysis of the following 
key efficacy variables: 
 
 
 
 
 
 
 
 
 
For the analysis of the main 
secondary efficacy variable 
(Section 4.2.1), subjects who 
started another AED, increased the 
dose or frequency of 
administration of an AED ongoing 
at the time the first BRV infusion 
started, or are switched to another 
AED, or have been administered 
any rescue medication for the 
treatment of ENS during the first 
3 hours after initiation of BRV 
treatment will be considered BRV 
nonresponders.  
For the analysis of the following 
secondary efficacy variables, 
subjects who started another AED, 
increased the dose or frequency of 
administration of an AED ongoing 
at the time the first BRV infusion 
started, or are switched to another 
AED, or have been administered 
any rescue medication for the 
treatment of ENS following the 
first 3 hours after initiation of 
BRV treatment will be considered 
BRV responders: 
• Absolute reduction in average 
seizure burden measured by 
continuous VEEG from 
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• Absolute and percentage 
reduction in average seizure 
burden measured by 
continuous VEEG from 
Baseline to the end of the 
96-hour Evaluation Period 
• Proportion of BRV 
responders during the 96-hour 
Evaluation Period (measured 
at the end of the 96-hour 
Evaluation Period) 
 
 
• Seizure freedom at the end of 
the Down-Titration Period 
(Confirmatory Cohorts only) 
 
• Proportion of subjects who 
are seizure-free by time 
interval at 3 hours, at 3-hour 
intervals thereafter through 24 
hours, and every 12 hour to 
24 hours following the start of 
the initial BRV treatment 
• Absolute and percent 
difference in clinical seizures 
at the end of the 24-hour 
Evaluation Period from 
Baseline to the end of the 96-
hour Evaluation Period 
• Percent reduction in average 
seizure burden measured by 
continuous VEEG from 
Baseline to the end of the 96-
hour Evaluation Period 
-Proportion of BRV 
responders at the end of the 
96-hour Evaluation Period  
 
• Seizure freedom at the end of 
the Down-Titration Period  
 
• Proportion of subjects who are 
seizure-free by time interval at 
3 hours, at 3-hour intervals 
thereafter through 24 hours, 
and every 12 hours to 24 hours 
following the start of the initial 
BRV treatment 
• Absolute difference in clinical 
seizures at the end of the 24-
hour Evaluation Period from 
Baseline for neonates with 
motor seizures at the time of 
inclusion 
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Baseline for neonates with 
motor seizures at the time of 
inclusion 
 
• Percent difference in clinical 
seizures at the end of the 24-
hour Evaluation Period from 
Baseline for neonates with 
motor seizures at the time of 
inclusion 
Section 10.2 
Assessment of 
other efficacy 
variables 
To further evaluate BRV efficacy, 
a descriptive comparison will be 
conducted of the main efficacy 
variable data from N01349 with 
published responder rates for 
MDZ (historical control group 
matched in age and condition) 
effective for the treatment of 
neonatal seizures in subjects of 
similar age (<29 days of postnatal 
age) and condition (neonatal 
seizures as noted in N01349 
eligibility criteria). A recent study 
(Weeke et al, 2016) provides 
response rates for second line 
MDZ treatment of neonatal 
seizures in a similar population 
and with primary endpoints 
comparable to N01349. 
To further evaluate BRV efficacy, 
a descriptive comparison will be 
conducted of the main efficacy 
variable data from N01349 with 
published responder rates for one 
or more AED treatments from 
literature (historical control group 
matched in age and condition) 
effective for the treatment of 
neonatal seizures in subjects of 
similar age (<29 days of postnatal 
age) and condition (neonatal 
seizures as noted in N01349 
eligibility criteria). A recent study 
(Weeke et al, 2016) provides 
response rates for second line 
AED treatment of neonatal 
seizures in a similar population 
and with primary endpoints 
comparable to N01349. 
Historical control changed from “MDZ” to 
“one or more AED treatments”  
 
Section 10.3 
Seizure 
burden 
Seizure burden is defined as the 
total minutes of ENS per hour. 
Seizure burden information will 
Seizure burden is defined as the 
total minutes of ENS per hour. 
Seizure burden information will be 
Clarification 
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Rationale 
be recorded via a continuous 
VEEG. Seizure burden at 
Baseline will be evaluated over a 
2-hour period. 
recorded for the Confirmatory 
Cohorts via a continuous VEEG. 
Seizure burden at Baseline will be 
evaluated over a period of at least 
1 hour (subjects with intermittent 
seizures) or up to 30 minutes 
(subjects in status epilepticus). 
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Section 
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Key components of amended text 
Rationale 
11.1.1.1 
Adverse event 
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. 
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 based 
on assessments performed prior to 
the first administration of BRV. 
Clarification 
Section 11.3.3
Vital signs 
Vital sign measurements, 
including systolic blood pressure, 
diastolic blood pressure, pulse 
rate, respiratory rate, oxygen 
saturation (pulse oximetry), and 
body temperature, should be 
measured at the study timepoints 
as described in… 
Vital sign measurements, 
including systolic blood pressure, 
diastolic blood pressure, pulse 
rate, respiratory rate (including 
apneas), oxygen saturation (pulse 
oximetry), and body temperature, 
should be measured at the study 
timepoints as described in… 
Text changes were made to provide 
consistent language throughout the 
protocol. 
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Section 
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Rationale 
Section 13.1 
Definition of 
analysis sets 
The Pharmacokinetic Per-
Protocol Set will consist of all 
subjects who provide at least 
1 measureable post-Baseline 
plasma sample (with recorded 
sampling time) on at least 
1 post-Baseline visit with 
documented study drug intake 
times. This analysis set will be 
used for the Exploratory Cohort 
and the Confirmatory Cohort(s). 
 
The Full Analysis Set will be 
used for the analysis of seizure 
data and will consist of all 
subjects in the SS who have a 
minimum of 2 hours of 
interpretable VEEG data from 
both the Baseline period and the 
first 3 hours of the post-Baseline 
period after initial BRV 
treatment. 
The Pharmacokinetic Per-Protocol 
Set will consist of all subjects who 
provide at least 1 measurable 
plasma sample (with recorded 
sampling time) on at least 
1 post-Baseline visit with 
documented study drug intake 
times. This analysis set will be 
used for the Exploratory Cohort 
and the Confirmatory Cohort(s). 
 
 
The Full Analysis Set will be used 
for the analysis of seizure data 
(efficacy) and will consist of all 
subjects in the SS who have a 
minimum of 2 hours of 
interpretable VEEG data from 
both the Baseline period and the 
first 3 hours of the post-Baseline 
period after initial BRV treatment. 
Clarification 
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Section 
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Rationale 
13.3.1 
Exploratory 
Cohort 
Based on the plasma samples 
collected for the Exploratory 
Cohort, relevant PK parameters 
including AUC, Cmax, volume of 
distribution, and clearance, will 
be estimated using 
noncompartmental methods. 
Based on the plasma samples 
collected for the Exploratory 
Cohort, relevant PK parameters 
including AUC, Cmax, volume of 
distribution, and clearance, will be 
estimated using noncompartmental 
methods, with sub-analysis by 
concomitant use of hypothermia. 
Text changes were made to provide 
consistent language throughout the 
protocol. 
Section 13.5.1 Title: Analysis of key efficacy 
variables 
Title: Analysis of secondary 
efficacy variables 
Text changes were made to provide 
consistent language throughout the 
protocol. 
Section 13.5.1
Analysis of 
the key 
efficacy 
variables 
The main efficacy variable is the 
proportion of responders to BRV 
treatment from Baseline to 
3 hours after the initial BRV 
dose.  
A BRV responder is defined as a 
subject who achieves at least 80% 
reduction in nonsevere seizure 
burden (“nonsevere” seizure 
burden being defined as ≤50% 
seizure activity on VEEG in any 
30-minute timespan), or at least 
50% reduction in severe seizure 
burden (“severe” seizure burden 
being defined as >50% seizure 
activity on VEEG in any 
30-minute timespan) compared to 
The main secondary efficacy 
variable is as follows: 
• Proportion of responders to 
BRV treatment from 
Baseline to 3 hours after 
the initial BRV dose.  
A BRV responder is defined as a 
subject who achieves the 
following reduction in seizure 
burden (ENS in minutes per hour) 
without need for rescue 
medication, compared to the 
seizure burden measured during 
the Baseline Period immediately 
prior to BRV administration, 
evaluated for a 2-hour period 
Text changes were made to provide 
consistent language throughout the 
protocol. 
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Section 
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Rationale 
the seizure burden measured 
during the 2-hour Baseline Period 
immediately prior to BRV 
administration, evaluated for a 
2-hour period starting 1 hour after 
the start of initial BRV treatment. 
Timespans of 30 minutes refer to 
the following intervals within the 
2-hour period: 0 to ≤30 minutes, 
>30 to ≤60 minutes, >60 to ≤90 
minutes, and >90 to ≤120 
minutes. The main efficacy 
variable will be analyzed using 
descriptive statistics. 
Baseline seizure burden is defined 
as seizure burden measured on 
the continuous VEEG (total ENS 
in minutes per hour) during a 
period of 2 hours immediately 
prior to the first administration of 
BRV. 
starting 1 hour after the start of 
initial BRV treatment: 
− At least 80% reduction in 
nonsevere seizure burden 
(Nonsevere seizure burden is 
defined as ≤50% seizure activity 
on VEEG in all 30-minute 
timespans) 
OR 
− At least 50% reduction in 
severe seizure burden 
(Severe seizure burden is defined 
as >50% seizure activity on VEEG 
in any 30-minute 
timespan).  Timespans of 30 
minutes refer to the following 
intervals within the 2-hour period: 
0 to ≤30 minutes, >30 to ≤60 
minutes, >60 to ≤90 minutes, and 
>90 to ≤120 minutes. 
For this study, an ENS is defined 
as an EEG seizure lasting for at 
least 10 seconds on VEEG. 
Baseline seizure burden is defined 
as seizure burden measured on the 
continuous VEEG (total ENS in 
minutes per hour) during a period 
of up to 1 hour immediately prior 
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Section 
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Subjects with at least 80% 
reduction in nonsevere seizure 
burden or at least 50% reduction 
in severe seizure burden from 
Baseline will be categorized as 
BRV responders. Subjects who 
drop out due to lack of BRV 
efficacy, are switched over to 
another AED treatment, or are 
administered any rescue 
medication (including BZDs) will 
be considered BRV 
nonresponders. 
to the first administration of study 
drug. 
 
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Section 
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Key components of amended text 
Rationale 
Section 13.5.1
Analysis of 
secondary 
efficacy 
variables 
For the Confirmatory Cohorts this 
means: 
• For the analysis of the main 
efficacy variable, subjects 
must not have used any rescue 
medication (including BZDs) 
during the first 3 hours after 
initiation of BRV treatment to 
be considered BRV 
responders. 
• For the analysis of the key 
efficacy variables (other than 
the main efficacy variable) 
and other efficacy variables, 
subjects must not have used 
>1 dose of rescue medication 
following the first 3 hours 
after initiation of BRV 
treatment to be considered 
BRV responders. A single 
dose of short-acting BZD as 
rescue medication is allowed, 
but only after 3 hours 
subsequent to the initiation of 
treatment with BRV. 
For the Confirmatory Cohorts this 
means: 
• For the analysis of the main 
secondary efficacy variable, 
subjects must not have used 
any rescue medication for the 
treatment of ENS during the 
first 3 hours after initiation of 
BRV treatment to be 
considered BRV responders. 
• For the analysis of the 
secondary efficacy variables 
(other than the main secondary 
efficacy variable) and other 
efficacy variables, subjects 
must not have used any rescue 
medication for the treatment of 
ENS following the first 3 hours 
after initiation of BRV 
treatment to be considered 
BRV responders. 
Text changes were made to provide 
consistent language throughout the 
protocol. 
Section 13.5.1
Analysis of 
secondary 
Descriptive statistics will be 
presented for the following key 
efficacy variables: 
Descriptive statistics will be 
presented for the following 
secondary efficacy variables: 
Text changes were made to provide 
consistent language throughout the 
protocol. 
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Section 
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Rationale 
efficacy 
variables 
• Absolute and percentage 
reduction in average seizure 
burden measured by 
continuous VEEG from 
Baseline to the end of the 96-
hour Evaluation Period 
• Proportion of BRV 
responders during the 96-hour 
Evaluation Period (measured 
at the end of the 96-hour 
Evaluation Period) 
 
 
• Absolute and percent 
difference in clinical seizures 
at the end of the 24-hour 
Evaluation Period from 
Baseline for neonates with 
motor seizures at the time of 
inclusion 
• Absolute reduction in average 
seizure burden measured by 
continuous VEEG from 
Baseline to the end of the 96-
hour Evaluation Period 
• Percent reduction in average 
seizure burden measured by 
continuous VEEG from 
Baseline to the end of the 96-
hour Evaluation Period 
• Proportion of BRV responders 
at the end of the 96-hour 
Evaluation Period 
• Absolute difference in clinical 
seizures at the end of the 
24-hour Evaluation Period 
from Baseline for neonates 
with motor seizures at the time 
of inclusion 
• Percent difference in clinical 
seizures at the end of the 
24-hour Evaluation Period 
from Baseline for neonates 
with motor seizures at the time 
of inclusion 
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Section 
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Key components of amended text 
Rationale 
Section 13.5.2
Analysis of 
the other 
efficacy 
variables 
• Absolute and percentage 
reduction from Baseline in 
seizure burden at evaluation 
periods of 0 hours to 3 hours, 
>3 hours to 6 hours, >6 hours 
to 12 hours, >12 hours to 24 
hours, >24 hours to 36 hours, 
>36 hours to 48 hours, 
>48 hours to 72 hours, and 
>72 hours to 96 hours after 
the start of initial BRV 
treatment 
 
• Absolute reduction from 
Baseline in seizure burden at 
evaluation periods of 0 hours 
to 3 hours, >3 hours to 6 hours, 
>6 hours to 12 hours, 
>12 hours to 24 hours, 
>24 hours to 36 hours, 
>36 hours to 48 hours, 
>48 hours to 72 hours, and 
>72 hours to 96 hours after the 
start of initial BRV treatment 
• Percentage reduction from 
Baseline in seizure burden at 
evaluation periods of 0 hours 
to 3 hours, >3 hours to 6 hours, 
>6 hours to 12 hours, 
>12 hours to 24 hours, 
>24 hours to 36 hours, 
>36 hours to 48 hours, 
>48 hours to 72 hours, and 
>72 hours to 96 hours after the 
start of initial BRV treatment 
Text changes were made to provide 
consistent language throughout the 
protocol. 
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Section 
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Key components of amended text 
Rationale 
Section 13.7 
Handling of 
dropouts or 
missing data 
For subjects who drop out during 
the Evaluation Period, the number 
of hours from the start of the 
Evaluation Period to the time of 
withdrawal (in hours) will be 
considered for analysis. Subjects 
in the Confirmatory Cohorts who 
drop out due to lack of BRV 
efficacy, are switched over to 
another AED treatment, or are 
administered >1 dose of rescue 
medication (including BZDs) 
following the first 3 hours after 
initial BRV treatment started will 
be considered BRV 
nonresponders.  
The impact of missing data on the 
assessment of the main efficacy 
variable will be evaluated with 
sensitivity analyses with further 
details to be included in the SAP. 
For subjects who dropped out 
during the Evaluation Period, the 
number of hours from the start of 
the Evaluation Period to the time 
of withdrawal (in hours) will be 
considered for analysis. Subjects 
in the Confirmatory Cohorts who 
started another AED, increased the 
dose or frequency of 
administration of an AED ongoing 
at the time the first BRV infusion 
started, or are switched to another 
AED, or have been administered 
any rescue medication for the 
treatment of ENS during the first 
3 hours after initiation of BRV 
treatment will be considered BRV 
nonresponders.  
The impact of missing data on the 
assessment of the main secondary 
efficacy variable will be evaluated 
with sensitivity analyses with 
further details to be included in the 
SAP. 
Clarification 
Section 13.8.1
Exploratory 
Cohort 
Not applicable 
During the DMC review of PK 
and safety data, the enrollment of 
subjects will be on hold. 
Clarification 
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Section 
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Key components of amended text 
Rationale 
Section 13.9 
No formal sample size calculation 
has been performed as a single 
treatment BRV arm is planned for 
descriptive summary of results 
and for comparison with the 6 
MDZ-treated subjects from the 
Exploratory Cohort. 
No formal sample size calculation 
has been performed as a single 
treatment BRV arm is planned for 
descriptive summary of results and 
for comparison with the 6 subjects 
from the Exploratory Cohort. 
Text changes were made to provide 
consistent language throughout the 
protocol. 
 
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17.6 
Protocol Amendment 6 
Rationale for the amendment 
The purpose of this non-substantial amendment is to correct minor inconsistencies of Protocol 
Amendment 5 identified after finalization.  
• Inconsistency concerning the use of LEV was corrected for the Exploratory Cohort. 
• Measurement of length before the first administration of BRV was erroneously removed 
from the Exploratory Cohort in Protocol Amendment 5, and this measurement has been 
re-inserted. 
• The text indicating that Investigators can consult the central reader to confirm seizures 
before subjects can enter the Evaluation Period was removed in Protocol Amendment 5 
from the Exploratory Cohort, but for clarity this has been re-inserted. 
The specific changes include the following: 
Change #1 
Sponsor Study Physician 
Added 
 to address 
Change #2 
Section 5.1 Study description 
N01349 consists of 2 steps including a comparison with a historical control group (matched in 
age and condition) treated with AEDs comparable SOC and diagnostic methods from literature 
will be used for the evaluation of efficacy. 
Has been changed to: 
N01349 consists of a 2-step design and includes a descriptive comparison with a historical 
control group (matched in age and condition) from literature treated with AEDs per SOC and 
diagnostic methods. 
Change #3 
Section 5.1.1 Exploratory Cohort 
The Screening Period starts up to 36 hours prior to the first administration of BRV. 
Phenobarbital, MDZ, PHT, LEV (≤ 60mg/kg/day), or LDC may have been administered prior to 
the subject’s enrollment into the study and/or at a location other than the study site. 
Has been changed to: 
The Screening Period starts up to 36 hours prior to the first administration of BRV. 
Phenobarbital, MDZ, PHT, LEV, or LDC may have been administered prior to the subject’s 
enrollment into the study and/or at a location other than the study site. 
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Change #4 
Section 5.1.1 Exploratory Cohort 
The following sentence was re-inserted: 
If preferred by the Investigator, the central VEEG reader can be consulted to confirm the 
required ENS. 
Change #5 
Section 5.2 Schedule of study assessments 
Table 5-1: 
Length during the Screening Period (immediately before first BRV administration) was re-
inserted as an assessment for the Exploratory Cohort. 
Change #6 
Section 8.1.1 Screening Period 
The following sentence was re-inserted: 
If preferred by the Investigator, the central VEEG reader can be consulted to confirm the 
required ENS. 
Change #7 
Section 8.1.1 Screening Period 
Length during the Screening Period (immediately before first BRV administration) was re-
inserted as an assessment. 
 
 
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17.7 
Protocol Amendment 7 
Rationale for the amendment 
The purposes of this substantial amendment are:  
• Update the protocol for the new UCB company name (UCB Biopharma SRL). 
• Specify the BRV dose recommended by the DMC for the Confirmatory Cohorts. 
• Incorporate the measures described in UCB’s COVID-19 Contingency Plan for N01349. 
• Prolong the BRV Extension Period for up to 90 days postnatal age for sites that may not be 
ready to transition subjects to EP0156 at the time that N01266 will be closed.  
• Correct minor inconsistencies and apply uniform terminology throughout the protocol. 
 
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Specific changes 
Section impacted 
Key components of previous 
text 
Key components of amended text 
Rationale 
Title page 
Study contact information 
Sponsor: UCB Biopharma 
SPRL 
Sponsor: UCB Biopharma SRL 
Sponsor name update 
Study contact information 
Pediatric Neonatologist: 
 
 
Pediatric Neonatologist: 
 
 
 
Change in DMC member 
Section 1, Summary 
Section 5.1, Study 
description  
Section 5.1.1, Exploratory 
Cohort 
Added text to specify the 
AEDs enrolled subjects will 
receive for the Exploratory 
and Confirmatory Cohorts per 
SOC. 
Per SOC, the AEDs include PB, MDZ, PHT, 
LEV, or LDC 
Alignment with text in Sections 
5.1.2 and 8.2.1 
Section 1, Summary 
Section 5.1, Study 
description 
Section 5.1.2, Confirmatory 
Cohort 
Section 5.4.2, Rationale for 
dose selection 
Section 7.2, Treatments to 
be administered 
Added details regarding 
determination of the BRV 
dose was determined by the 
DMC at a meeting held on 05 
Nov 2020. 
The BRV dose and frequency selected by the 
DMC for the Confirmatory Cohorts is 
1mg/kg bid (2mg/kg/day). Based on data 
from the Confirmatory Cohorts, the BRV 
dose may be further adjusted in a staggered 
approach per DMC discretion. 
Speci y the BRV dose for the 
Confirmatory Cohorts as selected 
by the DMC 
Section 1, Summary 
Section 2.3, Rationale for 
the study 
Section 5.4.1, Rationale for 
study design 
Section 6.1, Inclusion 
criteria 
Present current terminology 
for corrected gestational age 
(CGA). 
Removed all prior references to 
postmenstrual age (PMA) and replaced 
consistently with CGA. 
Consistency of terminology 
throughout the protocol 
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Section impacted 
Key components of previous 
text 
Key components of amended text 
Rationale 
Section 1, Summary 
No previous text. 
Added text describing the possible 
prolongation of the BRV Extension Period 
for sites in certain regions that must pause 
enrollment into N01349 from early Sep 2021 
onwards since they may not be ready to 
transition subjects to the long-term study 
(EP0156) at the time enrollment into N01266 
will be closed. 
Flexibility in allowing subjects to 
remain in N01349 until a long-
term study is available. 
Section 1, Summary 
Section 8.2.3, BRV 
Extension Period 
(Confirmatory Cohorts) 
Original text stated that the 
maximum study duration 
would be up to 75 days and 
the maximum BRV exposure 
would be up to 42 days. 
Clarified text to state that the maximum 
study duration and the maximum BRV 
exposure are expected to be up to 75 days 
and up to 42 days, respectively, for most 
subjects; the exceptions are subjects who 
remain in the Extension Period for a 
prolonged duration. New text added to 
provide the maximum study duration for 
subjects who remain in the study for up to 90 
days of PNA (ie, 130 days [90 days of PNA+ 
up to 7 days for the Down-Titration Period + 
up to 33 days for the Safety Follow-Up 
Period]) 
Provide study duration 
information for subjects who may 
remain in N01349 for a prolonged 
Extension Period. 
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Section impacted 
Key components of previous 
text 
Key components of amended text 
Rationale 
Section 4.3.2, Other safety 
variables  
Exploratory Cohort: 
Section 8.1.1, Screening 
Period 
Section 8.1.2, Evaluation 
Period 
Section 8.1.3.2, Extension 
Period 2 
Section 8.1.3.3, 
Unscheduled Visits 
Section 8.1.4, Safety 
Follow-Up Period 
Confirmatory Cohorts: 
Section 8.2.1.1, Baseline 
Period 
Section 8.2.2, Evaluation 
Period 
Section 8.2.3.2, Extension 
Period 2 
Section 8.2.3.3, 
Unscheduled Visits 
Section 8.2.4, Down-
Titration Period 
Section 8.2.5, Safety 
Follow-Up Period 
Heart rate and pulse rate were 
used interchangeably 
throughout the protocol. 
Heart rate to be presented consistently 
throughout. 
Consistency of terminology 
throughout the protocol 
Vital signs (blood pressure, 
pulse rate, respiratory rate, 
oxygen saturation [pulse 
oximetry] including apneas, 
and body temperature; at 0, 3, 
6, 12, 24, and 48 hours) 
Vital signs (blood pressure, heart rate, 
respiratory rate [including apneas], oxygen 
saturation [pulse oximetry], and body 
temperature; at 0, 3, 6, 12, 24, and 48 hours) 
Revised misleading wording to 
provide clarification on apneas 
Section 5.1, Study 
description 
Section 11.1.6 
A DMC will be in place for 
the duration of this study and 
will meet at no longer than 6-
Due to the low enrollment rate, the interval 
between DMC meetings may exceed 
6-month intervals, at the discretion of the 
DMC.  
Scheduling flexibility 
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Section impacted 
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Rationale 
month intervals between 
meetings. 
Section 5.1.2, Confirmatory 
Cohorts 
Section 7.2, Treatments to 
be administered 
The dose for subjects in the 
Confirmatory Cohort was yet 
to be determined.  
Subjects in the Confirmatory Cohorts will 
receive iv BRV 1mg/kg bid (2mg/kg/day), as 
recommended by the DMC on 05 Nov 2020. 
The DMC will continue to monitor the PK 
and safety of subjects and dosing may be 
further adjusted in a staggered approach as 
determined by the DMC.  
Updated the previous text to 
reflect the dose recommended by 
the DMC on 05 Nov 2020 and to 
note that the dose may be further 
adjusted per DMC discretion. 
Section 5.1.2, Confirmatory 
Cohorts 
Section 8.2.3, BRV 
Extension Period 
(Confirmatory Cohorts) 
The maximum anticipated 
duration of the BRV 
Extension Period per subject 
is up to 28 days of postnatal 
age (+7 days). 
In the event that a long-term study is 
temporarily not available, subjects are 
allowed to remain in the BRV Extension 
Period until they reach a PNA of up to 90 
days. For those subjects, the assessments 
planned for Unscheduled Visits (see Section 
8.1.3.3) will be conducted in intervals of 
approximately 30 days during the prolonged 
Extension Period. The treatment with BRV 
will be managed through IVRS. Before 
subjects can roll-over to the long-term study, 
they must have switched to BRV oral 
solution. 
Clarification that most subjects 
will remain in the BRV Extension 
Period for up to 28 (+7 days) of 
PNA but that subjects may have a 
prolonged Extension Period for 
up to 90 days of PNA if the long-
term study is not available at the 
time planned for the subject’s 
transition. 
Section 5.1.3, Study 
duration per subject 
The maximum study duration 
per subject is expected to be 
up to 75 days 
In the event that a long-term study is not 
available at the time of a subject’s planned 
transition, the maximum study duration for 
subjects who remain in the study for up to 90 
days of PNA and do not enter the long-term 
study will then be up to 130 days (90 days of 
PNA, up to 1 week for the Down-Titration 
Period, and up to 33 days for the Safety 
Follow-Up Period). 
Completeness; added maximum 
study duration for the subjects 
who remain for a prolonged BRV 
Extension Period. 
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Section impacted 
Key components of previous 
text 
Key components of amended text 
Rationale 
Section 5.1.3, Study 
duration per subject 
The maximum BRV exposure 
per subject is expected to be 
up to 42  days 
For subjects who remain in the study for up 
to 90 days of PNA and do not enter the long-
term study, maximum BRV exposure per 
subject is expected to be up to 97 days (up to 
90 days of PNA and up to 1 week for the 
Down-Titration Period). 
Completeness; added maximum 
BRV exposure for the subjects 
who remain for a prolonged BRV 
Extension Period. 
Section 5.2, Table 5-1 
Schedule of study 
assessments - Screening 
and Evaluation Periods 
(Exploratory Cohort) 
Medical history including 
Apgar score 
Medical history including Apgar score and 
HIE 
Clarification  
AED treatment 
Added the specific AEDs per SOC 
Clarification 
Footnote ‘j’: The recording of 
AEDs will include BZDs and 
opiates taken by the mother at 
the time of delivery. 
Added that COVID-19 vaccination will also 
be recorded as concomitant medication if the 
mother was pregnant or breastfeeding when 
vaccinated. 
Alignment with the BRV 
Program Contingency Plan. 
Section 5.2, Table 5-2 
Schedule of study 
assessments – Screening 
and Evaluation Periods 
(Confirmatory Cohorts) 
Medical history including 
Apgar score 
Medical history including Apgar score and 
HIE 
Clarification  
No previously included 
assessment for 
neurodevelopmental testing. 
Added the Bayley-III assessment at the 
96-hour timepoint of the Evaluation Period. 
Clarification that subjects 
completing the Evaluation Period 
in 28 days of PNA and directly 
roll over to the long-term study 
will require that the Bayley 
assessment be performed at the 
96-hour assessment of the 
Evaluation Period. 
Footnote ‘h’: Subjects are 
expected to receive IB BRV 
bid. The dose and dosing 
frequency of BRV will be 
adjusted based on the data 
collected for the analysis of 
the Exploratory Cohort. 
Subjects will receive iv BRV 1mg/kg bid 
(2mg/kg/day), as recommended by the DMC 
on 05 Nov 2020 based on the results of the 
PK analysis of the Exploratory Cohort as 
well as an existing PK model from N01263.  
Updated dose information based 
on DMC recommendation. 
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N01349 
 
 
 
 
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Section impacted 
Key components of previous 
text 
Key components of amended text 
Rationale 
Footnote ‘n’: The recording 
of AEDs will include BZDs 
and opiates taken by the 
mother at the time of 
delivery. 
Added that COVID-19 vaccination will also 
be recorded as concomitant medication if the 
mother was pregnant or breastfeeding when 
vaccinated.  
Alignment with the BRV 
Program Contingency Plan. 
Section 5.2, Table 5-3 
Schedule of study 
assessments - BRV 
Extension Period and 
Safety Follow-Up Period 
(Exploratory and 
Confirmatory Cohorts) 
Footnote ‘b’: Subjects will 
enter the Safety Follow-Up 
Period if they withdraw from 
the study at any time, or do 
not proceed to the BRV 
Extension Period, or complete 
the Down-Titration Period. 
This visit will occur 30±3 
days after the last 
administration of BRV. 
Added the following text to the existing 
footnote text: For subjects unable to return to 
the hospital due to COVID-19, the Safety 
Follow-up visit can be performed remotely. 
In this case vital signs, the physical and 
neurological examination, biometric and 
psychometric parameters, and the laboratory 
assessment may not be performed. 
Alignment with the BRV 
Program Contingency Plan. 
Footnote ‘k’: The recording 
of AEDs will include BZDs 
and opiates taken by the 
mother at the time of 
delivery. 
Added that COVID-19 vaccination will also 
be recorded as concomitant medication if the 
mother was pregnant or breastfeeding when 
vaccinated.  
Alignment with the BRV 
Program Contingency Plan. 
Confirmation/diagnosis of 
epilepsy is planned for EPV1 
and EPV2. 
Confirmation/diagnosis of epilepsy is only 
conducted at EPV2 to confirm that the 
subject qualifies for N01266 or EP0156.  
Correction and alignment across 
sections. 
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Section impacted 
Key components of previous 
text 
Key components of amended text 
Rationale 
Section 5.2, Table 5-3 
Schedule of study 
assessments - BRV 
Extension Period and 
Safety Follow-Up Period 
(Exploratory and 
Confirmatory Cohorts) 
Section 8.1.3.1, Safety 
Follow-Up Period 
(Exploratory Cohort) 
Section 8.2.3.1, Safety 
Follow-Up Period 
(Confirmatory Cohorts) 
Footnote ‘c’: Subjects will 
attend EPV1 at 7±2 days after 
completion of the Evaluation 
Period. 
Added the following text to the existing 
footnote text: For subjects unable to return to 
the hospital due to COVID-19, EPV1 can be 
performed remotely if BRV oral solution was 
dispensed at the time when the subject 
completed the Evaluation Period. 
Alignment with the BRV 
Program Contingency Plan. 
Section 5.2, Table 5-3 
Schedule of study 
assessments - BRV 
Extension Period and 
Safety Follow-Up Period 
(Exploratory and 
Confirmatory Cohorts) 
Section 8.2.3.3, 
Unscheduled Visits 
(Confirmatory Cohorts) 
No previous safety laboratory 
assessments were planned for 
Unscheduled Visits. 
Added footnote ‘n’ to state “Laboratory 
assessments (safety) only required for 
Unscheduled Visits performed during the 
BRV Extension Period. 
Added safety laboratory assessments 
(hematology, biochemistry, liver enzymes, 
and endocrinology) to Unscheduled Visits. 
Alignment with other BRV 
studies. 
Section 5.3, Schematic 
diagrams  
Figure 5-1, Schematic 
Overview of the study 
(Exploratory Cohort) 
Presents Evaluation Period as 
96 hours and is missing the 
Screening Period timeframe. 
The Evaluation Period is 48 hours and the 
Screening Period is up to 36 hours in 
duration. 
Error correction and addition of 
additional information 
Figure 5-2, Screening and 
Evaluation Periods 
(Exploratory Cohort) 
Administration of AED per 
SOC first line-, second line-, 
and third line-treatments 
Administration of one or more of the 
following AEDs: PB, MDZ, PHT, LEV, or 
LDC 
Consistency with updated text 
describing AED administration 
per SOC 
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Section impacted 
Key components of previous 
text 
Key components of amended text 
Rationale 
Figure 5-3, Schematic 
overview of the study 
(Confirmatory Cohorts) 
Missing Screening Period 
timeframe. 
 
Missing duration of BRV 
Extension Period for subjects 
with a prolonged duration of 
up to 90 days of PNA. 
The Screening Period is up to 36 hours in 
duration. 
 
Added duration of BRV Extension Period for 
subjects with a prolonged duration. 
Error correction 
 
 
New information. 
Figure 5-4, Screening and 
Evaluation Periods 
(Confirmatory Cohorts) 
Administration of AED per 
SOC first line-, second line-, 
and third line-treatments 
Administration of one or more of the 
following AEDs: PB, MDZ, PHT, LEV 
(≤60mg/kg/day), or LDC 
Consistency with updated text 
describing AED administration 
per SOC 
Section 6.2, Exclusion 
criteria 
Exclusion criterion #2: 
Subjects with seizures 
responding to previous AED 
treatment immediately prior 
to BRV treatment, pyridoxine 
treatment, or correction of 
metabolic disturbances 
(hypoglycemia, 
hypomagnesemia, or 
hypocalcemia) 
Subject with seizures responding to any of 
the following: previous AED treatment 
immediately prior to BRV treatment, 
pyridoxine treatment, or correction of 
metabolic disturbances (hypoglycemia, 
hypomagnesemia, or hypocalcemia). 
Clarify that previous pyridoxine 
treatment is not an exclusion 
criterion; subjects are excluded if 
they responded to pyridoxine 
treatment. 
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Section impacted 
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text 
Key components of amended text 
Rationale 
Section 7.2, Treatments to 
be administered 
Subjects in the Exploratory 
Cohort will be dosed with 
BRV (0.5mg/kg bid) 
according to the sites 
standard procedures. 
Administration of BRV is 
proposed as approximately 
15-minute iv infusions. 
Treatment with previous 
AEDs (PB, MDZ, PHT, 
LEV [≤60mg/kg/day], or 
LDC) is permitted to 
continue if the subject is on 
a stable dose from 1 hour 
prior to initiation of the 
BRV treatment. 
Subjects in the Exploratory Cohort will 
be dosed during the Evaluation Period 
with BRV (0.5mg/kg bid) according to 
the sites standard procedures. 
Administration of BRV is proposed as 
approximately 15-minute iv infusions. 
Treatment with previous AEDs (PB, 
MDZ, PHT, LEV [≤60mg/kg/day], or 
LDC) during the Evaluation Period is 
permitted to continue if the subject is on 
a stable dose from 1 hour prior to 
initiation of the BRV treatment. 
Clarify that the dosing of subjects 
in the Exploratory Cohort with 
BRV 0.5mg/kg bid will occur 
during the Evaluation Period. 
Clarify that treatment with 
previous AEDs is permitted 
during the Evaluation Period 
Section 8.1.3, BRV 
Extension Period 
(Exploratory Cohort) 
 
No previous text describing 
the purpose of the BRV 
Extension Period. 
The BRV Extension Period is intended to 
bridge the time until subjects are old enough 
to participate in the long-term study. 
Subjects completing the Evaluation Period at 
a PNA of at least 28 days may directly roll 
over to the long-term study, if they meet the 
eligibility criteria. Those patients are not 
required to enter the BRV Extension Period. 
Clarify the purpose of the BRV 
Extension Period 
Added text clarifying that 
subjects not continuing BRV 
treatment after the Evaluation 
Period will enter the Safety 
Follow-Up Period and not the 
BRV Extension Period 
Subjects not continuing the BRV treatment 
after they completed the Evaluation Period 
will not enter the BRV Extension Period but 
proceed immediately to the Safety 
Follow-Up Period 
Clarification of study design 
 
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Section impacted 
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text 
Key components of amended text 
Rationale 
Section 8.1.4, Safety 
Follow-Up Visit 
(Exploratory Cohort)  
Section 8.2.5, Safety 
Follow-Up Visit 
(Confirmatory Cohort)  
No previous text 
For subjects unable to return to the hospital 
due to COVID-19, the Safety Follow-Up 
Visit can be performed remotely. In this case 
vital signs, the physical and neurological 
examination, biometric and psychometric 
parameters, and the laboratory assessment 
may not be performed. 
Alignment with the BRV 
Program Contingency Plan. 
Section 8.2.2 Evaluation 
Period (Confirmatory 
Cohort) 
No previous text describing 
the number of doses 
administered in the 
Confirmatory Cohorts. 
Up to 8 iv doses of BRV (1mg/kg bid) will 
be administered as an approximately 
15-minute infusion during the 96-hour BRV 
Evaluation Period. 
Clarify the number of BRV doses 
administered in the Confirmatory 
Cohorts. 
Section 8.2.2 Evaluation 
Period (Confirmatory 
Cohort) 
BRV infusion (dose and 
dosing frequency of BRV to 
be confirmed after analysis of 
the data collected for the 
Exploratory Cohort). 
Text removed. 
Text no longer applicable since 
the DMC has determined the dose 
for the Confirmatory Cohorts 
Section 8.2.2 Evaluation 
Period (Confirmatory 
Cohorts) 
No previous text 
Added Bayley-III as an assessment to be 
performed following BRV administration 
during the Evaluation Period for subjects in 
the Confirmatory Cohort who are continuing 
into the long-term study and enrolled in 
countries where a validated translation is 
available. 
Clarification that subjects 
completing the Evaluation Period 
in 28 days of PNA and directly 
roll over to the long-term study 
will require that the Bayley 
assessment be performed at the 
96-hour assessment of the 
Evaluation Period. 
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Section impacted 
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text 
Key components of amended text 
Rationale 
Section 8.2.3 BRV 
Extension Period 
(Confirmatory Cohorts) 
No previous text describing 
the purpose of the BRV 
Extension Period. 
The BRV Extension Period is intended to 
bridge the time until subjects are old enough 
to participate in the long-term study. 
Subjects completing the Evaluation Period at 
a PNA of at least 28 days may directly roll 
over to the long-term study, if they meet the 
eligibility criteria. Those patients are not 
required to enter the BRV Extension Period. 
Clarify the purpose of the BRV 
Extension Period 
Subjects not entering the 
BRV Extension Period will 
proceed immediately to the 
Down-Titration Period (see 
Section 8.2.4). 
Subjects not continuing the BRV treatment 
after they completed the Evaluation Period 
will not enter the BRV Extension Period but 
proceed immediately to the Down-Titration 
Period 
Clarification 
Section 8.2.3.3, 
Unscheduled Visit 
(Confirmatory Cohort) 
No previous text 
For subjects who remain in the BRV 
Extension Period for a prolonged duration 
(ie, until they reach a PNA of 90 days), these 
assessments will be conducted at intervals of 
30 (±3 days). 
Provide the assessment schedule 
for subjects who remain for a 
prolonged BRV Extension Period. 
 
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18 
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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19 
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. 
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Approval Signatures
Name:
n01349-protocol-amend-7
Version:
2. 0
Document Number:
CLIN-000174213
Title:
n01349 Protocol Amendment 7
Approved Date:
25 May 2021
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 25-May-2021 14:37:55 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Subject Matter Expert
Date of Signature: 25-May-2021 14:40:08 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 25-May-2021 14:55:14 GMT+0000
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SAP_001.pdf: 
UCB 
 
13 May 2021 
Statistical Analysis Plan 
Brivaracetam 
N01349 
 
 
 
Confidential 
Page 1 of 58 
 
 
STATISTICAL ANALYSIS PLAN  
Study: N01349 
Product: Brivaracetam 
A MULTICENTER, OPEN-LABEL, SINGLE-ARM STUDY TO EVALUATE THE 
PHARMACOKINETICS, EFFICACY AND SAFETY OF BRIVARACETAM IN 
NEONATES WITH REPEATED ELECTROENCEPHALOGRAPHIC SEIZURES – 
PHASE 2/3 
 
SAP/Amendment Number Date 
Final SAP 
26 April 2018 
SAP Amendment 1 
17 July 2020 
SAP Amendment 2 
13 May 2021 
  
 
Confidentiality Statement 
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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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 6 
1 
INTRODUCTION ............................................................................................................. 8 
2 
PROTOCOL SUMMARY ................................................................................................. 8 
2.1 
Study objectives ............................................................................................................. 8 
2.1.1 
Primary objective ................................................................................................... 8 
2.1.2 
Secondary objectives ............................................................................................. 8 
2.2 
Study variables ............................................................................................................... 8 
2.2.1 
Pharmacokinetic variables (Exploratory and Confirmatory Cohorts) ................... 8 
2.2.1.1 
Primary PK variables ................................................................................... 8 
2.2.1.2 
Other PK variables ...................................................................................... 8 
2.2.2 
Efficacy variables (Confirmatory Cohorts only) ................................................... 8 
2.2.2.1 
Secondary efficacy variables ....................................................................... 9 
2.2.2.2 
Other efficacy variables ............................................................................... 9 
2.2.3 
Safety variables (Exploratory and Confirmatory Cohorts) .................................. 10 
2.2.3.1 
Secondary safety variable .......................................................................... 10 
2.2.3.2 
Other safety variables ................................................................................ 10 
2.3 
Study design and conduct ............................................................................................ 11 
2.3.1 
Exploratory cohort ............................................................................................... 12 
2.3.2 
Confirmatory Cohorts .......................................................................................... 13 
2.3.3 
Study duration per subject ................................................................................... 16 
2.4 
Determination of sample size ....................................................................................... 16 
3 
DATA ANALYSIS CONSIDERATIONS ...................................................................... 16 
3.1 
General presentation of summaries and analyses ........................................................ 16 
3.2 
General study level definitions .................................................................................... 17 
3.2.1 
Analysis time points ............................................................................................ 17 
3.2.1.1 
Relative day and time ................................................................................ 17 
3.2.1.2 
Relative day ............................................................................................... 18 
3.2.2 
Study periods for analysis .................................................................................... 18 
3.2.2.1 
Exploratory cohort study periods .............................................................. 18 
3.2.2.2 
Confirmatory Cohorts study periods ......................................................... 19 
3.2.3 
Mapping of assessments performed at Early Discontinuation Visit .................... 20 
3.2.4 
Definition of completed study ............................................................................. 20 
3.3 
Postnatal age (PNA), Gestational age (GA) and Corrected Gestational age (CGA) ... 20 
3.4 
Definition of Baseline values ....................................................................................... 20 
3.5 
Protocol deviations....................................................................................................... 21 
3.6 
Analysis sets................................................................................................................. 21 
3.6.1 
Safety Set ............................................................................................................. 21 
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3.6.2 
Full Analysis Set .................................................................................................. 21 
3.6.3 
Pharmacokinetic Per Protocol Set ....................................................................... 21 
3.7 
Treatment assignment and treatment groups ............................................................... 21 
3.8 
Center pooling strategy ................................................................................................ 21 
3.9 
Coding dictionaries ...................................................................................................... 21 
3.10 
Changes to protocol-defined analyses ......................................................................... 22 
4 
STATISTICAL/ANALYTICAL ISSUES ....................................................................... 22 
4.1 
Adjustments for covariates .......................................................................................... 22 
4.2 
Handling of dropouts or missing data .......................................................................... 22 
4.2.3 
Handling of dropouts or missing efficacy data .................................................... 24 
4.2.4 
Handling of study medication with missing data ................................................ 24 
4.2.5 
Potential impact of Coronavirus Disease 2019 on dropouts or missing data ...... 24 
4.3 
Interim analyses and data monitoring .......................................................................... 25 
4.4 
Multicenter studies ....................................................................................................... 25 
4.5 
Multiple comparisons/multiplicity ............................................................................... 25 
4.6 
Use of an efficacy subset of subjects ........................................................................... 25 
4.7 
Active-control studies intended to show equivalence .................................................. 25 
4.8 
Examination of subgroups ........................................................................................... 25 
5 
STUDY POPULATION CHARACTERISTICS ............................................................. 25 
5.1 
Subject disposition ....................................................................................................... 25 
5.2 
Protocol deviations....................................................................................................... 27 
6 
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................ 27 
6.1 
Demographics .............................................................................................................. 27 
6.2 
Medical history and concomitant diseases ................................................................... 28 
6.3 
Diagnosis of epilepsy ................................................................................................... 28 
6.4 
Prior and concomitant medications .............................................................................. 28 
6.4.1 
Medications at study entry ................................................................................... 28 
6.4.2 
Concomitant medications .................................................................................... 28 
6.4.3 
Non-AEDs taken at study entry ........................................................................... 29 
6.4.4 
Concomitant Non-AEDs ...................................................................................... 29 
6.4.5 
AEDs taken at study entry ................................................................................... 29 
6.4.6 
Concomitant AEDs .............................................................................................. 29 
6.5 
Procedure history ......................................................................................................... 29 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE ............................................... 29 
7.2 
Treatment compliance .................................................................................................. 30 
8 
EFFICACY ANALYSES ................................................................................................ 30 
8.1 
Endpoint definitions and derivations ........................................................................... 30 
8.1.1 
BRV responder and non-responder definitions ................................................... 30 
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8.1.2 
Baseline seizure burden ....................................................................................... 31 
8.1.2.1 
Baseline non-severe seizure burden .......................................................... 31 
8.1.2.2 
Baseline severe seizure burden .................................................................. 31 
8.1.3 
ENS definition ..................................................................................................... 31 
8.1.4 
Average per hour seizure burden (ENS in minutes per hour).............................. 31 
8.1.5 
Percent change in baseline seizure burden .......................................................... 31 
8.1.6 
Responder to other treatment ............................................................................... 32 
8.2 
Statistical analysis of the secondary efficacy variable ................................................. 32 
8.2.1 
Derivations of the main secondary efficacy variable........................................... 32 
8.2.2 
Analysis of the main secondary efficacy variable ............................................... 32 
8.2.3 
Sensitivity analysis of the main secondary efficacy variable .............................. 32 
8.2.4 
Derivations of the secondary efficacy variables .................................................. 33 
8.2.5 
Analysis of the secondary efficacy variables ....................................................... 35 
8.3 
Statistical analysis of other efficacy variables ............................................................. 35 
8.3.1 
Derivations of other efficacy variables ................................................................ 35 
8.3.2 
Analysis of other efficacy variables .................................................................... 37 
9 
PHARMACOKINETICS ................................................................................................. 37 
9.1 
Pharmacokinetics ......................................................................................................... 37 
9.1.1 
Exploratory Cohort .............................................................................................. 37 
9.1.2 
Confirmatory Cohorts .......................................................................................... 37 
10 SAFETY ANALYSES ..................................................................................................... 37 
10.1 
Extent of exposure ....................................................................................................... 38 
10.2 
Adverse events ............................................................................................................. 39 
10.2.1 
General summaries of AEs .................................................................................. 39 
10.3 
Clinical laboratory evaluations .................................................................................... 40 
10.3.1 
Hematology, Chemistry and Urinalysis Parameters ............................................ 40 
10.3.2 
Potential Drug Induced Liver Injury .................................................................... 41 
10.4 
Vital signs, physical findings, and other observations related to safety ...................... 41 
10.4.1 
Vital signs ............................................................................................................ 41 
10.4.2 
Hypothermia treatment ........................................................................................ 42 
10.4.3 
Mother’s use of AEDs ......................................................................................... 42 
10.4.4 
Sarnat scale .......................................................................................................... 42 
10.4.5 
Thompson score ................................................................................................... 42 
10.4.6 
N-PASS scale ....................................................................................................... 42 
10.4.7 
EEG parameters ................................................................................................... 43 
10.4.8 
Biometric parameters ........................................................................................... 43 
10.4.9 
Mechanical ventilation ......................................................................................... 43 
10.4.10 
Bayley-III® score ................................................................................................. 44 
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Statistical Analysis Plan 
Brivaracetam 
N01349 
 
 
 
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10.4.11 
Withdrawal and rebound phenomena .................................................................. 44 
10.5 
AED plasma level monitoring ..................................................................................... 44 
10.6 
Drug-Induced Liver Injury (DILI) ............................................................................... 44 
11 REFERENCES ................................................................................................................ 45 
12 APPENDICES ................................................................................................................. 46 
12.1 
Laboratory Parameters ................................................................................................. 46 
12.2 
Potentially clinically significant treatment-emergent criteria (PCST) for neonates 
(postnatal age up to 1 month)....................................................................................... 47 
12.2.1 
Blood pressure / vital signs .................................................................................. 48 
12.2.2 
Hematology parameters ....................................................................................... 49 
12.2.3 
Chemistry (without Bilirubin) ............................................................................. 50 
12.2.4 
Chemistry (Bilirubin) ........................................................................................... 50 
12.3 
PDILI ........................................................................................................................... 51 
13 AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN (SAP) ...................... 52 
13.1 
Change from Final SAP 26 April 2018 to SAP Amendment 1 ................................... 52 
13.2 
Change from SAP Amendment 1 to SAP Amendment 2 ............................................ 56 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE ..................................................... 58 
 
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Statistical Analysis Plan 
Brivaracetam 
N01349 
 
 
 
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Page 6 of 58 
LIST OF ABBREVIATIONS 
AC 
active control 
AE 
adverse event 
AED 
antiepileptic drug 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AUC 
area under the curve 
Bayley-III® 
Bayley scales of Infant and Toddler ®, Third Edition 
bid 
(bis in die) twice daily 
BRV 
brivaracetam 
BZD 
benzodiazepine 
CF 
conversion factor 
CGA 
corrected gestational age 
CI 
confidence interval 
CNS 
central nervous system 
COVID-19 
Coronavirus Disease 2019 
CRF 
case report form 
CSR 
clinical study report 
D 
day 
DBP 
diastolic blood pressure 
DEM 
Data Evaluation Meeting 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic case report form 
EEG 
electroencephalogram 
eg 
exempli gratia=for example  
EMA 
European Medicines Agency 
EMU 
epilepsy monitoring unit 
ENS 
electroencephalographic neonatal seizures 
EPV 
Extension Period Visit 
ER 
emergency room 
EudraCT 
European Union Drug Regulating Authorities Clinical Trial 
FAS 
Full Analysis Set 
GA 
gestational age 
H 
hour/-s 
HDL 
high-density lipoproteins 
HIE 
HR 
hypoxic-ischemic encephalopathy 
heart rate 
ICF 
Informed Consent form 
IPD 
important protocol deviations 
iv 
intravenous 
IVRS 
interactive voice response system 
LDC 
 lidocaine 
LEV 
levetiracetam 
LOQ 
limit of quantification 
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MDZ 
midazolam 
MedDRA© 
Medical Dictionary for Regulatory Activities© 
N-PASS 
Neonatal pain, agitation and sedation scale 
PB 
phenobarbital 
PCST 
possibly clinically significant treatment-emergent 
PDILI 
Potential drug-introduced liver injury  
PHT 
phenytoin 
PK 
pharmacokinetic 
PK-PPS 
Pharmacokinetic Per-Protocol Set 
PNA 
postnatal age 
PP 
per protocol 
PPS 
Per-Protocol Set 
PRO 
patient reported outcome 
PT 
preferred term 
RR 
respiratory rate 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SBP 
systolic blood pressure 
SD 
standard deviation 
SOC 
system organ class 
SS 
Safety Set 
t1/2 
elimination half-life 
TEAE 
treatment-emergent adverse event 
ULN 
upper limit of normal 
VEEG 
(multichannel) video-electroencephalography  
WHO-DRL 
World Health Organization Drug Reference List 
 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) defines the scope of the statistical analyses and provides a 
detailed description of statistical methodology for the statistical analyses to support the final 
clinical study report (CSR). The SAP is based on the following study document: N01349 
Protocol Amendment (6.0): 28 October 2019.  
2 
PROTOCOL SUMMARY 
2.1 
Study objectives 
2.1.1 
Primary objective 
The primary objective is to evaluate the pharmacokinetics (PK) of brivaracetam (BRV) in 
neonates who have seizures that are not adequately controlled with previous antiepileptic drug 
(AED) treatment, and to identify the optimal BRV dose (Exploratory cohort) for the treatment of 
subjects enrolled into the Confirmatory Cohorts of this study.   
2.1.2 
Secondary objectives 
The secondary objectives are: 
• To evaluate the efficacy of BRV in severe and non-severe seizure burden (defined by total 
minutes of electroencephalographic neonatal seizures (ENS) per hour) in neonates with 
seizures that are not adequately controlled with previous AED treatment 
• To evaluate the short-term safety and tolerability of BRV in neonates 
2.2 
Study variables 
2.2.1 
Pharmacokinetic variables (Exploratory and Confirmatory Cohorts) 
2.2.1.1 
Primary PK variables 
The primary PK variable is as follows: 
• Plasma concentrations of BRV following first dose on Day 1 
2.2.1.2 
Other PK variables  
• Plasma concentration of BRV on other occasions 
• Plasma concentrations of BRV metabolites ucb-42145 (acid), ucb-100406-1 (hydroxy), and 
ucb-107092-1 (hydroxyacid) 
• Area Under the Curve (AUC), t1/2, volume of distribution, and clearance of BRV 
• Plasma concentrations of concomitant AEDs if administered 3h (±1h) after start of the initial 
BRV administration 
2.2.2 
Efficacy variables (Confirmatory Cohorts only) 
The variables for the evaluation of BRV efficacy are described in Section 2.2.2.1  (Secondary 
efficacy variables) and Section 2.2.2.2 (Other efficacy variables). 
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2.2.2.1 
Secondary efficacy variables 
The main secondary efficacy variable is the proportion of responders to BRV treatment from 
Baseline to 3 hours after the initial BRV dose. Responders to BRV treatment is defined in 
Section 8.1. 
In addition, the secondary efficacy variables will include: 
• Proportion of subjects with at least 80% reduction in non-severe seizure burden from 
Baseline to 3 hours after the initial BRV treatment 
• Proportion of subjects with at least 50% reduction in severe seizure burden from Baseline to 
3 hours after the initial BRV treatment  
• Absolute reduction in average seizure burden measured by continuous video-
electroencephalography (VEEG) from Baseline to the end of the 96-hour Evaluation Period 
• Percent reduction in average seizure burden measured by continuous VEEG from Baseline to 
the end of the 96-hour Evaluation Period 
• Proportion of BRV responders at the end of the 96-hour Evaluation Period 
• Proportion of subjects who are seizure-free (100% reduction in seizure burden from 
Baseline) at 24 hours following the start of initial BRV treatment, categorized by subjects 
with non-severe or severe seizure burden at Baseline 
• Time to reduction in seizure burden for BRV responders (defined as the first time point when 
BRV responder criteria are met) 
• Seizure freedom at the end of the Down-Titration Period  
• Rate of at least 50% reduction in ENS frequency per hour from Baseline to the end of the 96-
hour Evaluation Period 
• Proportion of subjects who are seizure-free by time interval at 3 hours, at 3-hour intervals 
thereafter through 24 hours, and every 12 hours to 24 hours thereafter up until the end of the 
96-hour Evaluation Period following the start of the initial BRV treatment 
• Absolute difference in clinical seizures at the end of the 24-hour Evaluation Period from 
Baseline for neonates with motor seizures at the time of inclusion 
• Percent difference in clinical seizures at the end of the 24-hour Evaluation Period from 
Baseline for neonates with motor seizures at the time of inclusion 
2.2.2.2 
Other efficacy variables 
Other efficacy variables will include: 
• Absolute reduction from Baseline in seizure burden at evaluation periods of 0 hours to 3 
hours, >3 hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, >24 hours to 36 
hours, >36 hours to 48 hours, >48 hours to 72 hours, and >72 hours to 96 hours after the start 
of initial BRV treatment 
• Percentage reduction from Baseline in seizure burden at evaluation periods of 0 hours to 3 
hours, >3 hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, >24 hours to 36 
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hours, >36 hours to 48 hours, >48 hours to 72 hours, and >72 hours to 96 hours after the start 
of initial BRV treatment 
• Categorized percentage reduction from Baseline to the end of the 96-hour Evaluation Period 
in seizure burden (<-25% [worsening], -25% to <25% [no change], 25% to <50%, 50% to 
<80%, and ≥80%) 
• Proportion of BRV responders by time interval at evaluation periods of 0 hours to 3 hours, 
>3 hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, >24 hours to 36 hours, >36 
hours to 48 hours, >48 hours to 72 hours, and >72 hours to 96 hours after the start of initial 
BRV treatment 
• Proportion of subjects who switch over from BRV to another AED during the 96-hour 
Evaluation Period 
Proportion of responders to other treatment during the 96-hour Evaluation Period (including 
at the end of the 96-hour Evaluation Period, and by time intervals: 0 hours to 3 hours, >3 
hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, >24 hours to 36 hours, >36 
hours to 48 hours, >48 hours to 72 hours, and >72 hours to 96 hours after the start of initial 
BRV treatment) 
2.2.3 
Safety variables (Exploratory and Confirmatory Cohorts) 
2.2.3.1 
Secondary safety variable 
The secondary safety variable is as follows: 
• Adverse Events (AEs) as reported by the Investigator 
2.2.3.2 
Other safety variables 
• Change from Baseline in vital signs (blood pressure, heart rate, respiratory rate, oxygen 
saturation [pulse oximetry] including apneas, and body temperature) to 3, 6, 9, 12, 15, 18, 21, 
24, 48, 72 and 96 hours 
• Change from Baseline in safety laboratory tests to the end of the Evaluation Period 
• Change from Baseline in heart rate at 3 hours, 24 hours, 48 hours, and 96 hours after the start 
of initial BRV treatment  
• Change from Baseline in physical and neurological examination 24 hours, 48 hours, 72 
hours, and 96 hours after the start of initial BRV treatment (Sarnat scale; for subjects with 
hypoxic-ischemic encephalopathy (HIE) only) 
• Change from Baseline in electroencephalogram (EEG) parameters (assessment of sedation) 
to the end of the Evaluation Period (Confirmatory Cohorts only) 
• Change from Baseline in severity of HIE to the end of the Evaluation Period (Thompson 
score; for subjects with HIE only) 
• Change from Baseline in N-PASS score (neonatal pain and agitation measures) to the end of 
the Evaluation Period 
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• Change from Baseline in biometric parameters at the Safety Follow-Up Visit: length, body 
weight, and head circumference (head circumference Baseline measurement should be taken 
within 7 days prior to drug administration, or at birth for subjects ≤7 days old) 
• Withdrawal and rebound phenomena 
• Mechanical ventilation: 
− Number and percentage of subjects requiring mechanical ventilation during the 
Evaluation Period 
− Duration of mechanical ventilation during the Evaluation Period 
• Neurodevelopmental tests done after 1 year for subjects who enter the long-term follow-up 
study in countries where a validated translation of the Bayley Scales of Infant and Toddler 
development ®, Third Edition (Bayley-III ®) score is available. 
2.3 
Study design and conduct 
N01349 is a Phase 2/3, multicenter, open-label, single-arm study to evaluate the PK, efficacy, 
and safety of BRV in neonates with repeated EEG seizures. 
N01349 consists of a 2-step design and includes a descriptive comparison with a historical 
control group (matched in age and condition) from literature treated with AEDs per System 
Organ Class (SOC) and diagnostic methods. 
For the Exploratory Cohort (first step), enrolled subjects will receive one or more AEDs for the 
treatment of ENS per SOC (first-line, second-line, or subsequent treatment; choice of treatment, 
dose and dosing frequency are at the discretion of the Investigator) prior to receiving BRV. 
Subsequently, an initial iv dose of BRV (0.5mg/kg) will be administered. At the discretion of the 
Investigator, 3 additional iv BRV doses, up to a total of 4 iv BRV doses (0.5 mg/kg bid), can be 
administered during the 48-hour Evaluation Period. This treatment, which is the first use of BRV 
in neonates, is 4-fold less than the highest dose of 4mg/kg/day (2mg/kg bid) that has been used 
previously in infants ≥1 month old. 
For the Confirmatory Cohorts (second step), 3 consecutive cohorts are planned, and the efficacy 
of BRV will be evaluated. The iv dose of BRV selected for the Confirmatory Cohorts will be 
determined by the evaluation of BRV plasma concentrations from the Exploratory Cohort, as 
well as by previous PK modeling of N01263 data, to be within the range of plasma 
concentrations observed in children ≥1month old who received 4mg/kg/day. A dosage of BRV 
4mg/kg/day for neonates is predicted to be approximately equivalent to the highest BRV dosage 
(200mg/day) that has been studied in the adult Phase 3 program (eg, N01358 and N01258). The 
PK and safety of BRV will be evaluated in all cohorts. 
The recommendation to confirm or adjust the originally calculated BRV dose of the 
Confirmatory Cohorts of study N01349 will be given by the Data Monitoring Committee (DMC) 
after review of PK and safety data of the Exploratory Cohort. 
At the end of the Evaluation Period, subjects from both the Exploratory and Confirmatory 
Cohorts may enter the BRV Extension Period.   
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All subjects who participate in the BRV Extension Period must be offered entry into a long-term 
study, if they meet the eligibility criteria. Before entering the long-term study, subjects must be 
on oral BRV. 
If appropriate (in the event of screen failures), re-screening will be allowed for the study. Re-
screening for screen-failed subjects will be allowed with prior consultation of the Medical 
Monitor whenever feasible. Subjects can be re-screened only once. 
A continuous consent process will be followed. Continuous consent will be documented in the 
subjects’ medical charts and electronic Case Report form (eCRF). 
2.3.1 
Exploratory cohort 
For the Exploratory Cohort, at least 6 subjects who do not have adequate seizure control after 
they received one or more AEDs per SOC for the treatment of ENS (first-line, second-line, or 
subsequent treatment, which may have started prior to the subject’s admission into the study site; 
choice of treatment, dose and dosing regimen at the Investigator’s discretion) will be enrolled. 
The AED treatment per SOC can be continued when BRV dosing is initiated. Alternatively, 
another AED treatment (choice of treatment, dose, and dosing regimen at the Investigator’s 
discretion) must be initiated and continue in parallel with BRV treatment.  
At any time after AED treatment per SOC for the treatment of ENS (first-line, second-line, or 
subsequent treatment) was initiated, an initial low dose of BRV (0.5mg/kg [bid]) will be 
administered at the Investigator´s discretion. After the Exploratory Cohort completes the study, a 
PK and safety data review will be performed by the DMC. During the review of data from the 
Exploratory Cohort, the enrollment of subjects will be on hold. 
At least 2 subjects undergoing hypothermia treatment will be included. Subjects in the 
Exploratory Cohort might be replaced due to lack of data, as deemed necessary following the 
review of PK and safety data by the DMC.  
The study periods for the Exploratory Cohort are as follows:  
• Screening Period: from signing and dating of the written Informed Consent form (ICF) up to 
initiation of the first BRV dose.  
The Screening Period starts up to 36 hours prior to the first administration of BRV. 
Phenobarbital, midazolam (MDZ), phenytoin (PHT), levetiracetam (LEV), or lidocaine 
(LDC) may have been administered prior to the subject’s enrollment into the study and/or at 
a location other than the study site.  
Subjects will enter the Evaluation Period and start BRV treatment as soon as the occurrence 
of ENS per inclusion criterion 2a is confirmed by the Investigator based on local EEG. If 
preferred by the Investigator, the central VEEG reader can be consulted to confirm the 
required ENS. 
• Evaluation Period (48 hours): The first BRV infusion marks the starting point of the 
Evaluation Period. At any time after AED treatment per SOC for the treatment of ENS (first-
line, second-line, or subsequent treatment) was initiated, a low dose of BRV (0.5mg/kg) will 
be administered as an approximately 15-minute iv infusion; additional 3 doses of BRV 
(0.5mg/kg) can be administered every 12 hours for 48 hours (at the discretion of the 
Investigator). The AED treatment per SOC can be continued when BRV dosing is initiated. 
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Otherwise, another AED treatment (choice of treatment, dose, and dosing regimen at the 
Investigator´s discretion) must be initiated and continue in parallel with BRV treatment. 
Following the first BRV infusion, 3 to 6 PK blood microsamples (60μL/sample) will be 
collected during the 48-hour Evaluation Period from each subject for the determination of 
plasma concentrations of BRV and its metabolites. The number of subjects in the Exploratory 
Cohort may be increased, if deemed necessary following the analysis of PK data.  
At the end of the Evaluation Period, subjects who benefit from BRV treatment may enter the 
BRV Extension Period in accordance with the Investigator’s opinion. Subjects not entering 
the BRV Extension Period will proceed immediately to the Safety Follow-Up Period (a visit 
will occur 30±3 days after the final BRV administration).  
• BRV Extension Period (up to 28 days of postnatal age [+7 days]): Subjects can proceed to 
the BRV Extension Period if they benefit from BRV treatment during the Evaluation Period, 
in accordance with the Investigator’s opinion. All subjects who participate in the BRV 
Extension Period must be offered entry into the long-term study, if they meet the eligibility 
criteria. Subjects will participate in the BRV Extension Period until they reach a stable 
condition that will allow them to enter the long-term study. The anticipated duration of the 
BRV Extension Period per subject is up to 28 days of postnatal age (+7 days). Subjects must 
switch to BRV oral solution before entering the long-term study. The timing of the switch 
from iv to oral solution will be at the discretion of the Investigator; subjects who are not able 
to be dosed with BRV oral solution when they reach 28 days of postnatal age may continue 
in the BRV Extension Period for an additional 7 days; subjects who are not able to be 
switched to BRV oral solution by the end of the additional 7 days of the BRV Extension 
Period will not be eligible for enrollment in the long-term study.  
During the BRV Extension Period, subjects may continue receiving the same BRV dose 
administered at the end of the Evaluation Period (ie, BRV 0.5mg/kg bid); the BRV dose 
should not be increased but may be decreased at the discretion of the Investigator.  
• Safety Follow-Up Period: Subjects will proceed to the Safety Follow-Up Period if they do 
not enter the BRV Extension Period. The visit will occur 30±3 days after the final 
administration of BRV.  
• A DMC will be in place for the duration of this study. DMC Data Review Meetings to occur 
after completion of the 6 subjects in the Exploratory Cohort and after completion of each of 
the 3 Confirmatory Cohorts (12 subjects each), but no later than in intervals of 6 months. 
 
2.3.2 
Confirmatory Cohorts 
For the Confirmatory Cohorts, enrollment will only start after the dosing of BRV is determined 
based on the PK findings of the Exploratory Cohort and an existing PK model from N01263. A 
total of at least 36 subjects without adequate seizure control after receiving one or more of the 
following AEDs prior to or at the time of enrollment: PB, MDZ, PHT, LEV (≤60mg/kg/day), or 
LDC (first-line, second-line, or subsequent treatment, which may have started prior to the 
subject’s admission into the study site; dose and dosing regimen at the Investigator’s discretion) 
will enter the Confirmatory Cohorts. The AED treatment can be continued if the subject is on a 
stable dose for at least 1 hour at the time the first BRV infusion is initiated.  
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Three consecutive Confirmatory Cohorts (n=12 each) are planned; each cohort must have at least 
2 subjects undergoing hypothermia treatment. A PK and safety data review will be performed by 
the DMC after completion of each of the 3 Confirmatory Cohorts (12 subjects each), but no later 
than intervals of 6 months. During the PK and safety data review of data from the first and 
second Confirmatory Cohorts, the recruitment of subjects into subsequent cohorts will continue.  
The study periods for the Confirmatory Cohorts are as follows:  
• Screening Period: from signing and dating of the written ICF up to initiation of the first BRV 
dose.  
The Screening Period starts up to 36 hours prior to the first administration of BRV. 
Phenobarbital, MDZ, PHT, LEV (≤ 60mg/kg/day), or LDC may have been administered 
prior to the subject’s enrollment into the study and/or at a location other than the study site.  
• Baseline Period (included in the Screening Period):  
− For subjects with intermittent ENS: at least 1 hour prior to entering the Evaluation 
Period. 
− For subjects in status epilepticus: up to 30 minutes prior to entering the Evaluation 
Period. At least 15 minutes of continuous seizures, or 50% of cumulative seizure activity 
during a 30-minute interval are to be confirmed on EEG before the administration of 
BRV can start.  
As soon as subjects are considered to be in status epilepticus, steps required for the 
preparation of the initial BRV infusion can be initiated (eg, assignment of BRV kits 
through interactive response technology [IRT] and the dilution of BRV solution for iv 
infusion), even if the required EEG recording is not completed by that time.  
Status epilepticus in neonates for the purpose of this study is defined as follows: 
15 minutes of continuous or cumulative electrographic or electroclinical seizure within 
30 minutes 
The occurrence of ENS during the Baseline Period must be confirmed either by the local 
or central VEEG reader prior to BRV administration. Preferably, the central VEEG 
reader should confirm the required ENS. Video-EEGs that are acquired per standard of 
care prior to consenting and meet study-specific technical and quality requirements (eg, 
ability for immediate cloud-based central review) can be used as part of the Baseline 
assessment VEEG. 
• Evaluation Period (96 hours): The first administration of BRV marks the starting point of the 
Evaluation Period. All subjects will receive iv BRV. The BRV dose for subjects in the 
Confirmatory Cohorts will be determined based on the results of the PK analysis of the 
Exploratory Cohort (predicted to be approximately the BRV plasma concentrations in the 
same range as those observed at the highest recommended dose in older children and adults 
who receive BRV 200mg/day). If subjects do not benefit from BRV treatment after 96 hours 
of BRV administration, BRV administration will be stopped and replaced by another AED.  
Following the first BRV infusion, 6 PK blood microsamples (60μL/sample) will be collected 
during the 96-hour Evaluation Period for each subject for the determination of plasma 
concentrations of BRV and its metabolites. 
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The AED PK sample should be collected 3 hours after the start of the initial BRV 
administration. In addition, opportunistic blood samples for the PK analysis may be used at 
the Investigator’s discretion at any time during the Evaluation Period. 
At the end of the Evaluation Period, subjects who benefit from BRV treatment may enter the 
BRV Extension Period in accordance with the Investigator’s opinion. Subjects not entering 
the BRV Extension Period will proceed to the Down-Titration Period.  
• BRV Extension Period (up to 28 days of postnatal age [+7 days]): Subjects can proceed to 
the BRV Extension Period if they benefit from BRV treatment during the Evaluation Period, 
in accordance with the Investigator’s opinion. All subjects who participate in the BRV 
Extension Period must be offered entry into the long-term study, if they meet the eligibility 
criteria. Subjects will participate in the BRV Extension Period until they reach a stable 
condition that will allow them to enter the long-term study, if epilepsy is confirmed. The 
maximum anticipated duration of the BRV Extension Period per subject is up to 28 days of 
postnatal age (+7 days). Subjects must switch to BRV oral solution before entering the long-
term study. The time point of the switch from iv to oral solution will be at the discretion of 
the Investigator.  
Subjects who are not able to be dosed with BRV oral solution when they reach 28 days of 
postnatal age may continue in the BRV Extension Period for an additional 7 days; subjects 
who are not able to be switched to BRV oral solution by the end of the additional 7 days of 
the BRV Extension Period will not be eligible for enrollment in the long-term study.  
During the BRV Extension Period, subjects may continue receiving the same BRV dose 
administered at the end of the Evaluation Period; the BRV dose should not be increased, but 
may be decreased at the discretion of the Investigator.  
• Down-Titration Period (up to 1 week): A Down-Titration Period of up to 1 week is 
recommended for subjects in the Confirmatory Cohorts who discontinue BRV treatment 
prior to completion of the Evaluation Period, who do not proceed to the BRV Extension 
Period, or start the BRV Extension Period but do not enter the long-term study. The Down-
Titration steps and duration may be adjusted at the Investigator’s discretion.  
• Safety Follow-Up Period: Subjects will proceed to the Safety Follow-Up Period once they 
complete the Down-Titration Period. The visit will occur 30±3 days after the final 
administration of BRV.  
Rescue medication should be given if the following occurs:  
• There is no improvement in seizure burden within the first 3 hours after administration of 
BRV. 
• Seizure burden is unacceptable to the Investigator, in which case rescue medication can be 
given earlier at any time, but ideally not in the first 3 hours after the initial administration of 
BRV.  
Subjects in the Confirmatory Cohorts are allowed to switch over from BRV to another AED (eg, 
MDZ or PHT), if needed. Subjects discontinuing BRV treatment during the Evaluation Period 
should start the Down-Titration Period while completing the Evaluation Period in parallel for the 
full 96 hours. In this case, subjects will complete all study assessments, except the collection of 
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blood microsamples for the determination of BRV plasma concentrations. Ideally, changing or 
adding a new treatment should not occur during the first 3 hours after the initial administration of 
BRV. Subjects who are switched from BRV to another AED will not be eligible to participate 
either in the BRV Extension Period or the long-term study.  
2.3.3 
Study duration per subject 
The maximum study duration per subject will be up to 75 days (Screening Period [including 
Baseline Period (Confirmatory Cohorts only)], Evaluation Period, BRV Extension Period, 
Down-Titration Period [Confirmatory Cohorts only], and Safety Follow-Up Period). The 
individual study duration will be shorter depending on the type of cohort to which subjects will 
be assigned, the age at enrollment, and the decision to enter the BRV Extension Period.  
The maximum BRV exposure per subject will be up to 42 days, which comprises up to 4 days 
during the Evaluation Period (depending on type of cohort), up to 28 days (+7 days) of postnatal 
age during the BRV Extension Period, and up to 1 week during the Down-Titration Period for 
subjects in the Confirmatory Cohorts only.  
All subjects who do not continue into the long-term study will proceed to the Safety Follow-Up 
Period, and a visit will occur 30±3 days after the final dose of BRV.  
The end of the study is defined as the date of the last visit of the last subject in the study. 
2.4 
Determination of sample size 
At least 42 evaluable subjects will be enrolled in this study, with at least 6 subjects in the 
Exploratory Cohort and at least 36 subjects will be enrolled in 3 successive Confirmatory 
Cohorts, each consisting of 12 subjects. At least 2 subjects undergoing hypothermia treatment 
will be included in the Exploratory Cohort and each of the 3 Confirmatory Cohorts.  
Subjects in the Exploratory Cohort might be replaced due to lack of data, as deemed necessary 
following the review of PK and safety data by the DMC. 
No formal sample size calculation has been performed as a single treatment BRV arm is planned 
for descriptive summary results and for comparison with the 6 subjects from the Exploratory 
Cohort. The total number of at least 36 subjects in the Confirmatory Cohorts is expected to 
provide sufficient evidence of tolerability, safety, and efficacy, as well as good precision for the 
PK profile of BRV in neonates.   
Confirmatory Cohort subjects who drop out or are withdrawn from study participation will not 
be replaced. 
3 
DATA ANALYSIS CONSIDERATIONS 
3.1 
General presentation of summaries and analyses 
Statistical analysis and generation of tables, figures, subject data listings, and statistical output 
will be carried out using SAS® Version 9.3 or higher.  
Descriptive statistics, such as the number of subjects with available measurement (n), mean, 
standard deviation (SD), median, minimum value, and maximum value for quantitative variables, 
and counts and percentages for categorical variables, will be provided. Confidence intervals 
(95% CIs) will be provided for efficacy variables.  
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Unless otherwise noted, denominator for percentages will generally be based on the set of 
subjects with at least 1 assessment at the time point or at least 1 assessment during the time 
interval being summarized.  
Decimal places for descriptive statistics will always apply the following rules: 
• “n” will be an integer. 
• Mean, SD and median will use 1 additional decimal place compared to the original data. 
• Minimum and maximum will have the same number of decimal places as the original value. 
Unless otherwise noted, all percentages will be displayed to 1 decimal place. No percentage will 
be displayed for zero counts, and no decimal will be presented when the percentage is 100%.  
In general, descriptive summaries will be used to present study results overall (for the 
Confirmatory Cohorts) and by cohorts (Exploratory Cohort and each individual Confirmatory 
Cohort).  
Subject data listings will be provided and will present source data and key derived variables for 
statistical analyses. 
3.2 
General study level definitions 
3.2.1 
Analysis time points 
3.2.1.1 
Relative day and time 
For measurements with date and time collected, relative day and time will be calculated.  
Relative day and time in 24-h clock will be calculated as current date minus first dose date, 
current time in hours minus first dose time in hours, current time in minutes minus first dose time 
in minutes (add 1 minute if the current date and time is the same or after the first dose date and 
time).  
The relative time will be displayed in hours and minutes for relative times ≤24 hours before or 
after the first BRV administration. For relative times >24 hours the relative day and time will be 
calculated in days, hours and minutes. If the current date and time is the same as the first dose 
date and time, the relative time is 1 minute.  If the current date and time is prior to the first dose 
date and time, then the relative day and time will be denoted by “-”. If the current date and time 
is after the last dose date the relative day and time will be displayed with a leading “+”.  
The relative day and time in the tables and listings will be displayed in days, hours and minutes 
where applicable.   
− Example 1: first dose date and time is 5-Jan-2017: 10:30 am. The current date and time is 
5-Jan-2017: 8:45 am. The relative day and time is calculated as 5-Jan-2017 minus 5-Jan-
2017=0, 8:00 h – 10:00 h= -2:00 h, 45 min-30 min=15 min. The relative day and time is 0 
d 1 h 45 min and will be displayed as -1 h 45 min. 
− Example 2: first dose date and time is 5-Jan-2017: 10:30: am. The current date and time 
is 7-Jan-2017: 8:45 am. The relative day and time is calculated as 7-Jan-2017 minus 5-
Jan-2017=2 d (48 h), 8:00 h – 10:00 h= -2:00 h, 45 min-30 min + 1 min=16 min. The 
relative day and time is 1 d 22 h 16 min.  
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− Example 3: first dose date and time is 5-Jan-2017: 10:30 am. The current date and time is 
3-Jan-2017: 8:45 am. The relative day and time is calculated as 3-Jan-2017 minus 5-Jan-
2017= -2 d (-48 h), 8:00 h – 10:00 h= -2:00 h, 45 min-30 min=15 min. The relative day 
and time is -2 d 1 h 45 min.  
Relative day and time will not be calculated for partial dates and times. 
3.2.1.2 
Relative day 
For measurements with only date collected, relative day will be calculated. Relative day will be 
calculated as the date of first dose of study medication minus the current date for days prior to 
the first dose of study medication. During treatment (from the day of first study medication dose 
until the day of last study medication dose), relative day will be calculated as the current date 
minus the date of first dose of study medication plus 1 (eg, the day of first dose will be Day 1 
and the day prior to first dose will be Day -1). For days after the last dose of study medication, 
relative day will be calculated as the current date minus the date of last study medication dose 
and will include a ‘+’ to denote post-treatment days (eg, the day after the last dose will be Day 
+1). Relative day will not be calculated for partial dates. 
3.2.2 
Study periods for analysis 
3.2.2.1 
Exploratory cohort study periods 
3.2.2.1.1 
Screening Period 
The Screening Period will start on the date of the written informed consent form (ICF) and will 
end immediately prior to initiating the first BRV dose. The Screening Period starts up to 36 
hours prior to the first administration of BRV.  
3.2.2.1.2 
Evaluation Period 
Evaluation Period starts with the first BRV initiation and will end 48 hours after first BRV 
initiation. 
3.2.2.1.3 
BRV Extension Period 
If it is decided that the subject continues BRV administration after the Evaluation Period, the 
Extension Period starts after the end of the Evaluation Period. Subjects who will not attend the 
long term follow-up study, will have no Extension Period. 
If the subject will be enrolled in the long term follow up study, the end of the Extension Period is 
defined as last contact during N01349. In this case the maximum duration of the period will be 
35 days.  
In case subject attends the Extension Period but then it’s decided to stop the BRV administration, 
the subject will continue with the Safety Follow-up Period and the end of the Extension Period 
will be defined as the date and time of last BRV administration. 
Subjects not entering the BRV Extension Period will proceed immediately to the Safety Follow-
Up Period. 
The BRV Extension Period may consist of Extension Period Visit 1 (EPV1), Extension Period 
Visit 2 (EPV2), Unscheduled Visit and Telephone Contact. 
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3.2.2.1.4 
Safety Follow-Up Period 
Subjects will proceed to the Safety Follow-Up Period if they do not require further BRV 
administration. The start of the Safety Follow-up Period will be defined as after the end of the 
last BRV administration. The end of the Safety Follow-up Period will be defined as last contact 
to the subject, which will be the Follow-Up visit. This visit will occur 30±3 days after the final 
administration of BRV.  
3.2.2.2 
Confirmatory Cohorts study periods 
3.2.2.2.1 
Screening Period 
The Screening Period will start on the date of the written ICF and will end prior to initiating the 
first BRV dose. Screening Period includes Baseline Period described below. 
3.2.2.2.2 
Baseline Period 
Baseline Period (-1h to 0h) begins 1 hour before and ends immediately prior to the first initiation 
of BRV infusion. The Baseline Period is included in the Screening Period. 
3.2.2.2.3 
Evaluation Period 
Evaluation Period starts when the subject receives first dose of BRV infusion and will last for 96 
hours. If subjects do not benefit from BRV treatment after 96 hours of BRV administration, BRV 
administration will be stopped and replaced by another AED; however, the subject’s 
participation in the study will continue.  
3.2.2.2.4 
BRV Extension Period 
BRV Extension Period starts after the end of the Evaluation Period, subjects who benefit from 
BRV treatment may enter the BRV Extension Period in accordance with the Investigator’s 
opinion.  
If the subject will be enrolled in the long term follow up study, the end of the Extension Period is 
defined as last contact during N01349. In this case the maximum duration of the period will be 
35 days.  
In case subject attends the Extension Period but then it’s decided to not continue the BRV 
administration, the subject will continue with the Down Titration Period and the end of the 
Extension Period will be defined as the date and time of last stable dose of BRV infusion. 
Subjects not entering the BRV Extension Period will proceed immediately to the Down-Titration 
Period. 
The BRV Extension Period may consist of Extension Period Visit 1 (EPV1), Extension Period 
Visit 2 (EPV2), Unscheduled Visit and Telephone Contact.  
3.2.2.2.5 
Down Titration Period 
Down-Titration Period will start after the Evaluation Period or after the BRV Extension Period, 
can last up to 1 week. The end of the Down-Titration period is defined as day and time of last 
BRV administration. 
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3.2.2.2.6 
Safety Follow-Up Period 
Subjects will proceed to the Safety Follow-Up Period once they complete the Down-Titration 
Period. The end of the Safety Follow-up Period will be defined as last contact to the subject, 
which will be the Follow-Up visit. This visit will occur 30±3 days after the final administration 
of BRV. 
3.2.3 
Mapping of assessments performed at Early Discontinuation Visit 
Efficacy and safety assessments at an Early Discontinuation Visit (EDV) that corresponds to a 
scheduled visit will be summarized at the scheduled visit corresponding to the EDV if the 
assessment was scheduled to occur at that visit. Such assessments will also be considered for 
Last Value. In particular, vital signs, body weight, heart rate monitoring, laboratory parameters, 
PK samples and VEEG assessments are done at different time points of the Evaluation Period. 
All assessments of these variables at EDVs corresponding to a scheduled visit will be mapped to 
the corresponding scheduled visit. 
3.2.4 
Definition of completed study 
Subjects will be classified as completed the study if they complete the Safety Follow-up Visit or 
if they complete the Extension Period Visit 2 (EPV2) and continue BRV treatment in the Follow-
up study. 
 
3.3 
Postnatal age (PNA), Gestational age (GA) and Corrected 
Gestational age (CGA) 
PNA at the time of enrollment or the time elapsed after birth in days will be calculated as the 
date of signed inform consent minus the date of birth. 
GA will be calculated in weeks using PNA in weeks and CGA in weeks with the following 
formula: 
GA =  CGA –  PNA 
PNA in weeks will be calculated as PNA in days divided by 7 and rounded up to the nearest 
week. The PNA in weeks for subjects 7 days old and younger will be one week, for subjects aged 
more than 7 days old and less than or equal 14 days will be two weeks and so on. 
 
3.4 
Definition of Baseline values 
In general, baseline value for safety will be defined as the latest value prior to the first dose of 
BRV infusion, unless otherwise noted for a specific type of data. For almost all variables, this 
will be the assessment made at the Baseline visit. If a Baseline measurement is missing, and a 
Screening value available, the Screening value will be utilized as Baseline instead. If a Baseline 
assessment of biometric parameters (length, weight, head circumference) is taken on the same 
day as first dose of BRV infusion and assessment time is not known, the latest value at Screening 
or Baseline visit before or on the date of first dose of BRV infusion will be utilized as Baseline 
value. 
Both scheduled and unscheduled assessments are considered. 
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Baseline efficacy will be defined in the efficacy analysis section.  
3.5 
Protocol deviations 
Important protocol deviations (IPD) are deviations from the protocol that could potentially have 
a meaningful impact on key PK, efficacy, or safety outcomes for an individual subject. The 
criteria for identifying important protocol deviations and the classification of IPDs will be 
documented in a protocol-defined specification document. To the extent feasible, rules for 
identifying IPDs will be defined without review of the data and without consideration of the 
frequency of occurrence of such deviations. Whenever possible, criteria for identifying IPDs will 
be implemented algorithmically to ensure consistency in the classification of IPDs across all 
subjects.  
Important protocol deviations will be reviewed as part of the ongoing data cleaning process prior 
to database lock to confirm exclusion from the Pharmacokinetic Per-Protocol Set. 
3.6 
Analysis sets 
3.6.1 
Safety Set 
The Safety Set (SS) will consist of all enrolled subjects who take at least 1 dose of BRV. All 
safety analyses will be performed on the SS for the Exploratory Cohort and the Confirmatory 
Cohort(s). 
3.6.2 
Full Analysis Set 
The Full Analysis Set (FAS) will be used for the analysis of seizure data (efficacy) and will 
consist of all subjects in the SS who have a minimum of 2 hours of interpretable VEEG data 
from both the Baseline period and the first 3 hours of the post-Baseline period after initial BRV 
treatment.  
3.6.3 
Pharmacokinetic Per Protocol Set 
The Pharmacokinetic Per-Protocol Set (PK-PPS) will consist of all subjects who provide at least 
one measurable post-Baseline plasma sample (with recorded sampling time) on at least 1 post-
Baseline visit with documented study medication intake times. This analysis set will be used for 
the Exploratory Cohort and the Confirmatory Cohort(s). Subjects with important protocol 
deviations will be excluded from the PK-PPS. 
3.7 
Treatment assignment and treatment groups 
Because N01349 is an open-label, single-arm study, subjects will not be randomized to any 
treatment groups. The first 6 subjects meeting the eligibility criteria will be assigned to the 
Exploratory Cohort. Subsequent subjects will be assigned to the Confirmatory Cohorts. 
3.8 
Center pooling strategy 
There is no differentiation by center in this study, i.e. the data will be analyzed from all centers 
together. 
3.9 
Coding dictionaries 
Medical history (if available) and adverse events (AEs) will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA) version 18.1. Medications will be coded using 
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the World Health Organization Drug Dictionary (WHO-DD) version September 2017. Medical 
procedures will not be coded. 
3.10 
Changes to protocol-defined analyses 
Table 3.1: Changes to protocol-defined analyses 
Protocol-defined analyses 
New analyses 
Primary cause of seizure subgroups for the 
efficacy analysis are changed from the 
protocol defined:  
1. HIE, hemorrhage, or infarction 
2. CNS malformations;  
3. CNS infections;  
4. undetermined causes 
 
 
Primary cause of seizure subgroups based on 
the eCRF categories:  
1. HIE  
2. Ischemic stroke 
3. Intracranial hemorrhage 
4. Epileptic encephalopathy/genetic epilepsy 
5. Intracranial infection 
6. Brain malformation 
7. Inborn error of metabolism 
8. Undetermined cause 
9. Other 
 
4 
STATISTICAL/ANALYTICAL ISSUES 
4.1 
Adjustments for covariates 
Not applicable for this study. 
4.2 
Handling of dropouts or missing data 
There will be no specific imputation of missing data except for missing dates and/or times for 
concomitant medication and AE. 
The handling of missing dates and times for seizures if applicable will be discussed during the 
Data Evaluation Meeting (DEM). 
4.2.1 
Handling of prior and concomitant medications with missing data 
Any medications with incomplete start and end dates/times will be handled according to the 
following rules for classification as prior and concomitant and for the calculation of relative 
study days. Such imputations will only be performed for these classifications and calculations; in 
the listings all data will be shown as recorded on the electronic Case Report Form (eCRF). 
Imputation of Partial Start Dates: 
• If only the month and year are specified and the month and year of first dose is not the same 
as the month and year of the start date, then use the 1st of the month. 
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• If only the month and year are specified and the month and year of first dose is the same as 
the month and year of the start date, then use the date of first dose. 
• If only the year is specified, and the year of first dose is not the same as the year of the start 
date, then use January 1 of the year of the start date. 
• If only the year is specified, and the year of first dose is the same as the year of the start date, 
then use the date of first dose. 
• If the date is completely unknown, then use the date of first dose. 
Imputation of Partial End Dates: 
• If only the month and year are specified, then use the last day of the month. 
• If only the year is specified, then use December 31 of that year. 
• If the date is completely unknown, do not impute the stop date. 
There will be no imputation of any other missing data. 
4.2.2 
Handling of adverse events with missing data 
Any AEs with incomplete onset and outcome (end) dates/times will be handled according to the 
following rules for classification as treatment-emergent. Such imputations will only be 
performed for these classifications; in the listings all data will be shown as recorded on the 
eCRF. 
• If only the month and year are specified and the month and year of first dose is not the same 
as the month and year of onset, then use the 1st of the month. 
• If only the month and year are specified and the month and year of first dose is the same as 
the month and year of onset, then use the date/time of first dose. 
• If only the year is specified, and the year of first dose is not the same as the year of onset, 
then use January 1 of the year of onset. 
• If only the year is specified, and the year of first dose is the same as the year of onset, then 
use the date/time of first dose. 
• If the AE onset date is completely unknown, then use the date of first dose. 
• Imputations for missing end dates/times will not be performed for classification as treatment-
emergent as this is not required. 
Adverse events with missing severity or causality will be regarded as ‘severe’ and ‘related’ 
respectively for the tabulations. There will be no imputation of any other missing data. Any AE 
with additional missing data that prohibits classification for a given tabulation will be excluded 
from that tabulation. 
In case of uncoded AEs, these AEs should be designated as “UNCODED” at all MedDRA 
levels, and such AEs will be included in summary tables and subject listings based on this 
classification. 
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4.2.3 
Handling of dropouts or missing efficacy data  
For subjects who drop out during the Evaluation Period, the number of hours from the start of the 
Evaluation Period to the time of withdrawal (in hours) will be considered for analysis. Subjects 
in the Confirmatory Cohorts who are withdrawn or are switched over to another AED treatment 
prior to the Evaluation Period or are administered >1 dose of rescue medication (including 
BZDs) following the first 3 hours after initial BRV treatment started will be considered BRV 
non-responders.  
4.2.4 
Handling of study medication with missing data 
No imputation should be performed for missing study medication start dates. This field on the 
eCRF should not be partial or missing. 
For partial or missing date of last dose of study medication, the following imputation rules will 
be applied for the purpose of calculating overall exposure: 
• If the day is missing (but month and year available), impute the last dose date as the 
minimum of the last day of the month or the date of last contact reported on the trial 
termination CRF; if day and month are both missing (only year available), impute the last 
dose date as the minimum of the last day of the year or the date of last contact on the trial 
termination CRF. 
• If a subject died and has a partial or missing last administration date, the date is to set to the 
date of death. If there is a partial date of last dose and the month/year are prior to the month 
and year of the date of death, follow partial date imputation rules. 
• If the last dose date is completely missing and no information could be obtained from data 
cleaning exercises, the last dose date should be imputed as the date of last contact per the 
study termination CRF. A review of the data for subjects with completely missing last dose 
dates should be performed to ensure that the imputation does not result in an unrealistic value 
for duration of exposure.  
• If the time is missing, set the time to 00:00 
Imputed date of last dose dates should only be used for calculation of the duration of exposure. 
The date as recorded on the eCRF should be presented in subject data listings (no imputed dates 
should be included in subject data listings). 
4.2.5 
Potential impact of Coronavirus Disease 2019 on dropouts or 
missing data  
The Coronavirus Disease 2019 (COVID-19) pandemic may cause disruption in the conduct of 
ongoing clinical trials including treatment and study withdrawals, subjects missing study visits, 
and/or visits being performed remotely instead of at site. Therefore, for subjects enrolled after 30 
May 2020, an additional eCRF page will be foreseen. Sites will complete this page in case a 
subject was impacted by COVID-19 during the study. The COVID-19 Impact eCRF page will 
include the timing and impact of COVID-19, and relationship to COVID-19 (ie, whether the 
subject has confirmed/suspected COVID-19 infection, or whether the impact was related to 
general circumstances around COVID-19 without infection). 
 
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4.3 
Interim analyses and data monitoring 
No formal interim analysis is planned for this study; however, PK and safety data will be 
presented to and reviewed by a DMC. The DMC will oversee the PK and safety of the study by 
reviewing the PK and safety data periodically, in order to evaluate the risk-benefit profile in 
relation to the overall progress of the study. The DMC will make recommendations regarding 
subject safety and continuance of the study based on the observed risk-benefit of the emerging 
data; however, no formal statistical stopping rules will be defined.  
The DMC will perform interim reviews of the PK and safety data to ensure subject safety. The 
first DMC meeting to review safety data will occur after the Exploratory Cohort (6 subjects) 
completed the study. The remaining DMC meetings will take place after completion of each of 
the 3 Confirmatory Cohorts (12 subjects each) but no later than in intervals of 6 months between 
meetings. 
The DMC or Sponsor can convene an ad hoc DMC meeting to review the data and make 
recommendations on the continuation or modification of the study. The objectives and 
procedures for the DMC will be detailed in the DMC Charter. A DMC SAP will be developed 
and will capture analysis needed for DMC.  
4.4 
Multicenter studies 
The results will not be presented by individual center. 
4.5 
Multiple comparisons/multiplicity 
Not applicable for this study. The study is not statistically powered, and all analyses are of 
descriptive nature. No statistical tests will be performed. 
4.6 
Use of an efficacy subset of subjects 
The efficacy analysis will be based on the FAS subjects from the Confirmatory Cohorts.  
The efficacy evaluation at the end of the Down-Titration Period will be based on the subset of 
subjects in the Confirmatory Cohorts who enter the Down-Titration Period. 
4.7 
Active-control studies intended to show equivalence 
Not applicable for this study. 
4.8 
Examination of subgroups 
All efficacy variables will be analyzed by  
1. Primary cause of seizure subgroups: HIE, ischemic stroke, intracranial hemorrhage, epileptic 
encephalopathy/genetic epilepsy, intracranial infection, brain malformation, inborn error of 
metabolism, undetermined causes, other. 
2. Concomitant use of hypothermia subgroups: yes, no. 
5 
STUDY POPULATION CHARACTERISTICS 
5.1 
Subject disposition 
The number of screen failures and the primary reason for screen failure will be summarized for 
all enrolled subjects (ie, all subjects with the signed informed consent). 
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Disposition of subjects screened will be summarized overall and by sites: the date of first subject 
in, date of last subject out (latest scheduled or unscheduled visit), and the number of enrolled 
subjects will be summarized for all study sites and by study site. Additionally, the number of 
subjects in each of the SS, FAS and PK-PPS will be summarized overall and by cohorts. 
Disposition and Discontinuation Reasons by Periods 
• Subjects started study 
• Subjects entered treatment 
• Subjects completed study 
• Subjects discontinuing the study and primary reason for discontinuation 
• Subjects started Screening Period 
• Subjects completed Screening Period 
• Subjects discontinuing the study during the Screening Period and primary reason for 
discontinuation 
• Subjects started Evaluation Period 
• Subjects completed Evaluation Period 
• Subjects discontinuing the Evaluation Period and primary reason for discontinuation 
• Subjects entering BRV Extension Period 
• Subjects switching to Oral Solution prior to entering the BRV Extension Period 
• Subjects completed BRV Extension Period 
• Subjects qualifying to enter the Long-Term Follow-up study 
• Subjects discontinuing during the BRV Extension Period and primary reason for 
discontinuation 
• Subjects entering Safety Follow-Up Period and not entering BRV Extension Period  
• Subjects entering Down-Titration Period and not entering BRV Extension Period 
(Confirmatory Cohorts) 
• Subjects completed Down-Titration Period (Confirmatory Cohorts) 
• Subjects discontinuing during the Down-Titration Period and primary reason for 
discontinuation (Confirmatory Cohorts) 
• Subjects entering Safety Follow-Up Period after completing Down-Titration Period 
(Confirmatory Cohorts) 
All percentages will be relative to the number of enrolled subjects. 
Discontinuation due to Adverse Events 
A summary of discontinuations due to AEs for the SS will present the number and percentage of 
subjects who discontinued this study due to AEs overall, and by type of AE. 
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Listings of study eligibility criteria text, of subjects who did not meet study eligibility criteria, of 
subject disposition and of subject analysis sets will be provided for all subjects screened. 
5.2 
Protocol deviations 
The number and percentage of FAS subjects with no important protocol deviations and at least 
1 important protocol deviation will be summarized overall, and by main category of protocol 
deviation (Inclusion criteria deviation, Exclusion criteria deviation, Withdrawal criteria 
deviation, Prohibited concomitant medication, use incorrect treatment or dose, Treatment non-
compliance, Procedural non-compliance). Additionally, the number and percentage of subjects 
excluded from the PK-PPS due to important protocol deviations will be summarized overall and 
by main protocol deviation category for the FAS. Other specific categories of protocol deviations 
will be defined within the IPD specifications document. 
Listing of subjects excluded from PK-PPS will be provided. 
Listing of important protocol deviations will be provided for the SS. 
All completed COVID-19 Impact eCRF pages and other IPDs will be discussed in IPD meetings, 
including whether the deviation may have been caused by COVID-19.   
All data collected from the COVID-19 Impact eCRF page will be listed only. 
 
6 
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS 
6.1 
Demographics 
Demographic summaries will be presented for the FAS, PK-PPS and SS overall and by cohorts. 
The variables to be considered are: 
• Corrected gestational age  
• Postnatal age (as defined in Section 3.3) 
• Gestational age (as defined in Section 3.3) 
• Gestational age category (Pre-term <37 weeks vs Full term ≥37 weeks) 
• Gender 
• Weight (g) 
• Length (cm) 
• Head circumference (cm) 
• Racial group (American Indian/Alaskan Native, Asian, Black, Native Hawaiian or Other 
Pacific Islander, White, and Other/Mixed) 
• Country  
• Apgar score (1 minute) 
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• Apgar score (5 minutes) 
• HIE status 
The listing of demographics including Apgar score will be provided for all subjects screened.   
6.2 
Medical history and concomitant diseases 
The number and percentage of subjects with a medical history (if available) condition including 
both resolved and ongoing conditions at the time of study entry will be summarized overall and 
by MedDRA primary system organ class (SOC) and preferred term (PT) for the SS.  
Listing of medical history glossary and medical history (if available) will be provided for the SS.  
6.3 
Diagnosis of epilepsy 
Listing of diagnosis of epilepsy will be provided for the SS. 
6.4 
Prior and concomitant medications 
Each medication recorded on the Prior and Concomitant Medication eCRF will be classified as 
either an AED or a non-AED medication based on the coded Preferred Drug Name. Medications 
which pharmacologically can be classified as an AED but which were taken for non-epilepsy 
indications may also be classified as AEDs. Identification of medications as a non-AED or AED 
will be done using the UCB file: 
AEDs_ATCs_SEP2017_FINAL_benzo_groups_23JUL2019.xls. The classification of such 
medications will be confirmed prior to database lock. Listing of prior and concomitant 
medications indicating whether medication is AED or not will be provided for the SS. Glossary 
of all prior and concomitant medications indicating AED and non-AED medications will be 
provided for the SS. 
For the summarization, similar AEDs are grouped and summarized together. For example: 
Valproate includes valproate sodium, valproate semisodium, valproate bismuth, valproate 
magnesium, valpromide, ergenyl chrono, valproic acid; Phenytoin includes phenytoin sodium, 
phenytoin calcium, mephenytoin, zentronal, metetoin, ethotoin, albutoin, hydantal, phelantin, 
hydantol D, anirrit, dintoinale, fosphenytoin sodium, phenytoin, fosphenytoin, hydantoin 
derivatives, hydantoin; Phenobarbital includes phenobarbital sodium, methylphenobarbital, 
metharbital, alepsal, phenobarbital, kaneuron, epanal, phenobarbital calcium, phenobarbital 
diethylamine, phenobarbital magnesium, phenobarbital quinine. Benzodiazepine AEDs that can 
be grouped by Bromazepam, Alprazolam, Cloxazolam, Diazepam group, Chlordiazepoxide, 
Clonazepam, Clobazam, Lorazepam, Clotiazepam, Temazepam, and Clorazepate are considered 
the same AED at the group level. Combination AEDs are not considered for grouping. 
6.4.1 
Medications at study entry 
Medications with the start date and time prior or equal to the date of signed informed consent are 
considered medications at study entry. 
6.4.2 
Concomitant medications 
Medications that were taken on at least one day in common with the study medication dosing 
period regardless of the start and stop date and time are defined as concomitant medications. This 
definition includes 1) medications with the start date and time taken after the first dose of study 
medication but prior to the last dose of study medication, 2) medications with the start date and 
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time prior to the date and time of the first dose of study medication but with the stop date and 
time after the first dose of study medication. 
 
6.4.3 
Non-AEDs taken at study entry 
The number and percentage of subjects taking non-AED medications at the time of study entry 
will be summarized overall and by WHO-DRL pharmacological group (Anatomical Therapeutic 
Chemical [ATC] classification level 1), therapeutic subgroup (ATC classification level 2) and 
preferred drug name for the SS. Subject data listing for non-AED taken at study entry will be 
provided for the SS. 
6.4.4 
Concomitant Non-AEDs 
The number and percentage of subjects taking concomitant non-AEDs will be summarized 
similar to non-AEDs at study entry for the SS. Subject data listing for concomitant non-AED will 
be provided for the SS. 
6.4.5 
AEDs taken at study entry 
The number and percentage of subjects taking AEDs at the time of study entry will be 
summarized by WHO-DRL preferred drug name for the SS.  Subject data listing for AED taken 
at study entry will be provided for the SS. 
 
6.4.6 
Concomitant AEDs 
The number and percentage of subjects taking concomitant AEDs will be summarized by WHO-
DRL preferred drug name for the SS. Subject data listing for concomitant AED will be provided 
for the SS. 
6.5 
Procedure history 
Listing of procedure history will be provided for the SS. 
6.6 
Concomitant medical procedures 
Listing of concomitant medical procedures will be provided for the SS. 
6.7 
Primary cause of seizure 
Primary cause of seizure will be summarized by cohorts for SS. The summary analysis of the 
primary cause of seizure should be based on the latest data collected per subject prior to study 
completion/termination. Listing of all primary causes of seizure will be provided for the SS. 
7 
MEASUREMENTS OF TREATMENT COMPLIANCE 
7.1 
Drug accountability 
Listing of drug accountability for oral solution during the BRV Extension Period will be 
provided for the SS.  
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7.2 
Treatment compliance 
Treatment compliance will be analyzed for iv BRV administered during the study Evaluation 
Period. Treatment compliance will be calculated per subject per infusion for iv BRV. 
Noncompliance will be recorded for subjects who are administered <80% or >120% of the 
planned BRV dose. 
Compliance will be calculated as 100 times the actual dose given during the infusion at particular 
time point based on the Study Drug Administration CRF and dividing this quantity by the 
planned infusion dose at that time point. For the Exploratory Cohort, planned iv BRV dose will 
be calculated as 0.5 mg times body weight (kg) per subject per infusion per time point. The last 
weight measurement prior to the first BRV dose will be taken for this calculation.  
For the Confirmatory Cohorts, planned iv BRV dose (mg/kg) will be determined based on the 
evaluation of BRV plasma concentrations from the Exploratory Cohort. 
Treatment compliance will also be analyzed for BRV Extension Period, the planned dose for oral 
BRV is the same dosage administered at the end of the Evaluation Period (i.e., BRV 0.5mg/kg 
bid for the Exploratory Cohort). The BRV dose should not be increased but can be decreased at 
the discretion of the Investigator. Therefore, noncompliance will be recorded only for subjects 
who are administered >120% of the planned oral BRV dose.  For the Confirmatory Cohorts, the 
planned dose will be also the same dosage administered at the end of the Evaluation Period.  
Listing of the calculated treatment compliance will be provided for the SS.  
8 
EFFICACY ANALYSES 
Efficacy analyses will be performed using FAS subjects from the Confirmatory Cohorts only. 
Only the Overall Confirmatory Cohort will be used for efficacy interpretations. Efficacy 
parameters will be summarized descriptively (with 95% CIs) by individual Confirmatory 
Cohorts and for all combined Confirmatory Cohorts. In addition, all efficacy variables will be 
analyzed by the latest primary cause of seizure (see categories in Section 4.8) and concomitant 
use of hypothermia and reported for each subject using data listings. 
Seizure efficacy data may also be transformed if needed. The transformation of seizure data to be 
used (if needed) will be log (x + 1) where x is the neonate seizure count or the seizure burden. 
8.1 
Endpoint definitions and derivations 
8.1.1 
BRV responder and non-responder definitions 
A BRV responder is defined as a subject who achieves the following reduction in seizure burden 
(ENS in minutes per hour) without need for rescue medication, compared to the seizure burden 
measured during the Baseline Period immediately prior to BRV administration, evaluated for a 
2-hour period starting 1 hour after the start of initial BRV treatment: 
• At least 80% reduction (≥80 percent change) in non-severe seizure burden 
(Non-severe seizure burden is defined as ≤50% seizure activity on video-
electroencephalography (VEEG) in all 30-minute timespans) 
OR 
• At least 50% reduction (≥50 percent change) in severe seizure burden 
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(Severe seizure burden is defined as >50% seizure activity on VEEG in any 30-minute 
timespan. Timespans of 30 minutes refer to the following intervals within the 2-hour period: 
0 to ≤30 minutes, >30 to ≤60 minutes, >60 to ≤90 minutes, and >90 to ≤120 minutes.)  
Subjects not meeting the BRV responder definition are classified as BRV non-responders. In 
addition, subjects who drop out due to lack of BRV efficacy, are switched over to another AED 
treatment, or are administered any rescue medication (any treatment initiation with a new AED, 
or any increase of dose or frequency of an existing concomitant AED for the treatment of 
seizures during the Evaluation Period - including BZDs) during the first 3 hours after initiation 
of BRV treatment will be considered BRV non-responders. 
8.1.2 
Baseline seizure burden  
Baseline seizure burden is defined as seizure burden measured on the continuous VEEG (total 
ENS in minutes per hour) during a period of up to 1 hour immediately prior to the first 
administration of study medication. 
8.1.2.1 
Baseline non-severe seizure burden 
Baseline non-severe seizure burden is defined as seizure activity (total ENS duration in minutes) 
for ≤ 15 minutes in all of the following 30-minute time periods: 0-30 and >30-60 minutes during 
the 1-hour Baseline Period. For example, if total ENS duration of 18 minutes occurred as 9 
minutes of ENS duration in each of any two 30-minute time periods or 18 minutes of ENS are 
distributed over several 30 minute time intervals so that the ENS duration in each interval is ≤15 
minutes, then the baseline seizure burden is non-severe. 
8.1.2.2 
Baseline severe seizure burden 
Baseline severe seizure burden is defined as seizure activity (total ENS duration in minutes) for 
>15 minutes in at least one of the following 30-minute time periods 0-30 and >30-60 minutes 
during the up to 1-hour Baseline Period. For example, if total ENS duration is 18 minutes and the 
distribution of ENS duration is 16 minutes in 0-30 minutes time period and 2 minutes in >30-60 
minutes time period, then the baseline seizure burden is severe. 
8.1.3 
ENS definition 
For this study, an ENS is defined as an electroencephalographic (EEG) seizure lasting for at least 
10 seconds on VEEG.  
8.1.4 
Average per hour seizure burden (ENS in minutes per hour)  
Average per hour seizure burden per subject (ENS in minutes per hour) is defined as total seizure 
burden measured over a period of time (in minutes) divided by the number of hours in the given 
period of time.  That is all seizure activity times (durations in minutes) will be added up across 
the Evaluation Period.  It will then be divided by the total duration of the Evaluation Period to 
calculate a seizure burden value in minutes per hour.  Average seizure burden value will be 
calculated during the Baseline period and the Evaluation Period (and transformed the data by 
taking log (x +1) for both Baseline and the Evaluation Period if needed). 
8.1.5 
Percent change in baseline seizure burden  
Percent change in baseline seizure burden is defined as a difference between average per hour 
seizure burden at baseline (calculated over the 1-hour baseline period) and average per hour 
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seizure burden calculated over given period of time after the start of initial BRV treatment 
divided by the average per hour seizure burden at baseline and multiplied by 100.  
If the percent change is ≥80% (reduction in baseline) and baseline seizure burden is non-severe 
or if the percent change ≥50% (reduction in baseline) and baseline seizure burden is severe then 
this subject is defined as BRV responder. No rounding will be applied, one decimal will be 
considered for comparison (for example, if the percent change is 79.999%, then consider 1 
decimal as 79.9% which is less than 80%). 
8.1.6 
Responder to other treatment 
Responder to other treatment is defined as subject who stopped BRV or switched from BRV to 
act as a rescue medication and achieved at least 80% reduction (≥80 percent change) in non-
severe seizure burden from start of other treatment to end of other treatment or at least 50% 
reduction (≥50 percent change) in severe seizure burden measured from initiation of other 
treatment to end of other treatment during the 96-hour Evaluation Period. Baseline Period for 
other treatment is defined as 1 hour prior to starting the other treatment. Other treatment 
Evaluation Period is from the start to the end of other treatment or to the end of 96-hour 
Evaluation Period if other treatment end is after the 96-hour Evaluation Period.  
8.2 
Statistical analysis of the secondary efficacy variable 
8.2.1 
Derivations of the main secondary efficacy variable 
The main secondary efficacy variable is the proportion of responders to BRV treatment from 
Baseline to 3 hours after the initial BRV dose. The numerator is the number of BRV responders 
for main secondary efficacy variable defined in Section 8.1. The denominator is defined as the 
number of the subjects in the FAS from Confirmatory Cohorts. 
8.2.2 
Analysis of the main secondary efficacy variable 
The main secondary efficacy variable will be summarized using descriptive statistics (counts and 
proportions with the 95% CIs). See Section 3.1 for the details. Subgroup analysis of main 
secondary efficacy variable will be produced for the latest primary cause of seizure (see 
categories in Section 4.8) and concomitant use of hypothermia. Listing of main secondary 
efficacy variable will be provided. 
To further evaluate BRV efficacy, a descriptive comparison will be conducted of the main 
secondary efficacy variable data from N01349 with published responder rates for MDZ 
(historical control group matched in age and condition) effective for the treatment of neonatal 
seizures in subjects of similar age (<29 days of postnatal age) and condition (neonatal seizures as 
noted in N01349 eligibility criteria). A recent study (Weeke et al, 2016) provides response rates 
for second line MDZ treatment of neonatal seizures in a similar population and with primary 
endpoints comparable to N01349. Results from this study, as well as results from other studies 
available in the literature at the time of N01349 completion and with populations and efficacy 
endpoints comparable to N01349, will be used for these descriptive comparisons.  
A listing of main secondary efficacy variable will be provided for the FAS. 
8.2.3 
Sensitivity analysis of the main secondary efficacy variable 
The impact of missing data on the assessment of the main secondary efficacy variable will be 
evaluated with sensitivity analyses. Subjects who drop out for reasons other than due to lack of 
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BRV efficacy, are switched over to another AED treatment, or are administered any rescue 
medication (including BZDs) will be excluded from the analysis. 
The numerator of the main secondary efficacy variable is defined as the number of responders to 
BRV treatment from Baseline to 3 hours after the initial BRV dose (see Section 8.1 for the 
definition of BRV responders). Subjects, who dropped out for reasons other than due to lack of 
BRV efficacy, are switched over to another AED treatment or received any rescue medication 
during the first 3 hours after the initiation of BRV treatment will be excluded from the analysis. 
The denominator is defined as the number of the FAS subjects in the Confirmatory Cohorts with 
the following subjects excluded: subjects who dropped out for reasons other than due to the lack 
of BRV efficacy reasons, are switched to another AED or received any rescue medication 
(including BZDs) during the first 3 hours after the initiation of BRV treatment. 
8.2.4 
Derivations of the secondary efficacy variables 
The following secondary efficacy variables are defined as follows:  
• Proportion of subjects with at least 80% reduction in non-severe seizure burden from 
Baseline to 3 hours after the initial BRV treatment [derivations: see the definition of baseline 
non-severe seizure burden in Section 8.1.2.1; reduction of at least 80% in non-severe seizure 
burden from baseline is defined as a ≥80% difference between average per hour seizure 
burden at baseline (calculated over the 1-hour Baseline Period) and average per hour seizure 
burden calculated over 3 hours after the start of initial BRV treatment divided by the average 
per hour seizure burden at baseline and multiplied by 100. The numerator is defined as the 
number of subjects with the 80% reduction described above. The denominator is defined as 
the number of subjects in the FAS from Confirmatory Cohorts with baseline non-severe 
seizure burden.] 
• Proportion of subjects with at least 50% reduction in severe seizure burden from Baseline to 
3 hours after the initial BRV treatment [derivations: see the definition of baseline severe 
seizure burden in Section 8.1.2.2; reduction of at least 50% in severe seizure burden from 
baseline is defined as a ≥50% difference between average per hour seizure burden at baseline 
(calculated over the 1-hour Baseline Period) and average per hour seizure burden calculated 
over 3 hours after the start of initial BRV treatment divided by the average per hour seizure 
burden at baseline and multiplied by 100. The numerator is defined as the number of subjects 
with the 50% reduction described above. The denominator is defined as the number of 
subjects in the FAS from Confirmatory Cohorts with baseline severe seizure burden.]  
• Absolute reduction in average seizure burden measured by continuous VEEG from Baseline 
to the end of the 96-hour Evaluation Period [derivations: see the definition of baseline 
seizure burden and of average per hour seizure burden in Section 8.1, average per hour over 
96-hour Evaluation Period seizure burden is calculated as the total seizure burden during the 
96-hour Evaluation Period divided by 96, the number of hours in the Evaluation Period, 
average per hour seizure baseline seizure burden is calculated as the total seizure burden over 
1-hour Baseline Period divided by 1. The absolute reduction in average per hour seizure 
burden is defined as the average per hour seizure burden at the end of the 96-hour Evaluation 
Period minus average per hour baseline seizure burden] 
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• Percentage reduction in average seizure burden measured by continuous VEEG from 
Baseline to the end of the 96-hour Evaluation Period [derivations: see the definition of 
baseline seizure burden and of average per hour seizure burden in Section 8.1, average per 
hour over 96-hour Evaluation Period seizure burden is calculated as the total seizure burden 
during the 96-hour Evaluation Period divided by 96, the number of hours in the Evaluation 
Period, average per hour seizure baseline seizure burden is calculated as the total seizure 
burden over 1-hour Baseline Period divided by 1. The percentage reduction is defined as the 
absolute reduction in average per hour seizure burden divided by the average per hour 
baseline seizure burden and multiplied by 100.] 
• Proportion of BRV responders during the 96-hour Evaluation Period (measured at the end of 
the 96-hour Evaluation Period) [derivations: see the definition of BRV responders for other 
than main efficacy variable in Section 8.1, the post-baseline seizure burden will be evaluated 
during the last 1 hour1 of the 96-hour Evaluation Period, the denominator is defined as the 
number of subjects in the FAS from Confirmatory Cohorts.]  
• Proportion of subjects who are seizure-free (100% reduction in seizure burden from Baseline, 
i.e. those subjects whose seizure burden disappeared) at 24 hours following the start of initial 
BRV treatment, categorized by subjects with non-severe or severe seizure burden at Baseline 
[derivations: the numerator is the number of subjects with 100% reduction in seizure burden 
from Baseline or no ENS during the last 2 hours of the 24-hour time period following the 
start of initial BRV treatment, see the definition of baseline seizure burden in Section 8.1, the 
denominator is defined as the number of subjects in the FAS from Confirmatory Cohorts.] 
• Time to reduction in seizure burden for BRV responders (defined as the first time point when 
BRV responder criteria are met ) [derivations: the time to reduction in seizure burden is 
measured in hours, defined as the first time point (date and time) when BRV responder 
criteria are met minus the date and time of the first BRV dose, event is defined as response to 
BRV, subjects will be evaluated for response at the following time points: 3 hours, 4 hours, 5 
hours, etc. , 96 hours after the initial BRV dose. Response will be calculated referring to the 
last 1 hour prior to the time point. Non-responder for the analysis of other than main efficacy 
variable subjects defined in the Section 8.1 are censored with time to censoring defined as the 
date and time of the event defining the non-responder status (drop out due to lack of BRV 
efficacy, switch over to another AED treatment,  used >1 dose of rescue medication 
following the first 3 hours after initiation of BRV treatment) or date and time of the end of 
the Evaluation Period in case there are no events of response or non-response minus the date 
and time of first BRV dose; when the time is not collected, use HH:MM=23:59.]  
• Seizure freedom at the end of the Down-Titration Period (Confirmatory Cohorts only) 
[derivations: defined as proportion of subjects who are seizure-free at the end of the Down-
Titration Period, the numerator is the number of subjects with seizure-freedom defined as no 
ENS at the end of the Down-Titration Period, i.e. no ENS during 1 hour of VEEG, the 
denominator is defined as the number of subjects in the FAS from Confirmatory cohorts with 
VEEG data at the end of the Down-Titration Period.] 
• Rate of at least 50% reduction in ENS frequency per hour from Baseline to the end of the 96-
hour Evaluation Period [derivations: the numerator is defined as the number of subjects with 
the 50% reduction in ENS frequency, i.e. the difference between the average ENS frequency 
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per hour at Baseline and the average ENS frequency per hour over the 96-hour Evaluation 
Period divided by the average per hour Baseline ENS frequency and multiplied by 100 
should be at least 50%, the denominator is defined as the number of subjects in the FAS from 
Confirmatory Cohorts. Average per hour ENS frequency at Baseline is calculated as the total 
number of ENS over 1-hour Baseline Period divided by 1; average per hour ENS frequency 
at the end of the 96-hour Evaluation Period is defined as the number of ENS over 96-hour 
Evaluation Period divided by 96.] 
• Proportion of subjects who are seizure-free by time interval at 3 hours, at 3-hour intervals 
thereafter through 24 hours, and every 12 hours to 24 hours following the start of the initial 
BRV treatment [derivations: the numerator is defined as the number of subjects with no ENS 
or 100% reduction in seizure burden from Baseline to 3 hours after the first BRV dose and 
then with no seizure burden at 6, 9, 12, 15, 18, 21, 24, 36, 48, 60, 72, 84, 96 hours after the 
first BRV dose, the 2 hours of VEEG prior to the defined time point will be evaluated for 
seizure freedom/ENS absence; the denominator is defined as the number of subjects in the 
FAS from Confirmatory Cohorts, see the definition of reduction in seizure burden from 
Baseline in Section 8.1.] 
• Absolute difference in clinical seizures (annotated by central reader) at the end of the first 
24-hour of the 96-hour Evaluation Period from Baseline for neonates with motor seizures at 
the time of inclusion [derivations: absolute difference is defined as the difference between 
the number of clinical seizures observed during the 1-hour Baseline Period and the number of 
post-baseline clinical seizures observed during the 1 hour prior to the end of the 24-hour 
Evaluation Period]  
• Percent difference in clinical seizures (annotated by central reader) at the end of the first 
24 hour of the 96-hour Evaluation Period from Baseline for neonates with motor seizures at 
The Time of Inclusion [Derivations: Percent Difference is Defined as the Absolute 
Difference in Clinical Seizures (Defined Above) Divided by the Number of Clinical Seizures 
During The Baseline Period and Multiplied by 100.] 
8.2.5 
Analysis of the secondary efficacy variables 
Categorical secondary efficacy variables will be summarized using descriptive statistics (counts 
and proportions with the 95% CIs). Continuous key efficacy variables will be analyzed 
descriptively as described in Section 3.1. 
Time to reduction in seizure burden will be summarized descriptively by individual 
Confirmatory Cohorts and for all combined Confirmatory Cohorts, the cumulative number of 
events (response to BRV), Kaplan-Meier estimates at each hour during the Evaluation Period and 
median time to seizure burden reduction with 95% confidence interval will be provided. Also, 
graphical displays of Kaplan-Meier curves will be provided for each cohort separately.  
A listing of secondary efficacy variables will be provided for the FAS. 
8.3 
Statistical analysis of other efficacy variables 
8.3.1 
Derivations of other efficacy variables 
The other efficacy variables are defined as follows: 
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• Absolute and percentage reduction from Baseline in seizure burden at evaluation periods of 0 
hours to 3 hours, >3 hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, >24 hours 
to 36 hours, >36 hours to 48 hours, >48 hours to 72 hours, and >72 hours to 96 hours after 
the start of initial BRV treatment [derivations: see the definition of baseline seizure burden 
and of average per hour seizure burden in Section 8.1, the absolute reduction is defined as 
the difference between the baseline average per hour seizure burden and average per hour 
seizure burden at evaluation periods of 0 hours to 3 hours, >3 hours to 6 hours, >6 hours to 
12 hours, >12 hours to 24 hours, >24 hours to 36 hours, >36 hours to 48 hours, >48 hours to 
72 hours, and >72 hours to 96 hours after the start of initial BRV treatment. The percentage 
reduction is defined as the absolute reduction in seizure burden divided by the baseline 
average per hour seizure burden and multiplied by 100.] 
• Categorized percentage reduction from Baseline to the end of the 96-hour Evaluation Period 
in seizure burden (<-25% [worsening], -25% to <25% [no change], 25% to <50%, 50% to 
<80%, and ≥80%) [Derivations: The percentage reduction of seizure burden is defined as 
the difference between the average per hour baseline seizure burden and the average per hour 
seizure burden at the end of the 96-hour Evaluation Period divided by the average per hour 
baseline seizure burden and multiplied by 100. For the definition of the average per hour 
seizure burden, please see Section 8.1.] 
• Proportion of BRV responders by time interval at evaluation periods of 0 hours to 3 hours, 
>3 hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, >24 hours to 36 hours, >36 
hours to 48 hours, >48 hours to 72 hours, and >72 hours to 96 hours after the start of initial 
BRV treatment [derivations: see the definition of BRV responders in Section 8.1, for the 
numerator calculate the number of responders during the given above evaluation periods 0-3 
hours, >3-6 hours, >6-12 hours, >12-24 hours, >24-36 hours, etc., the denominator is defined 
as the number of subjects in the FAS from Confirmatory Cohorts.]  
• Proportion of subjects who are switched over from BRV to another AED during the 96-hour 
Evaluation Period [derivations: for the numerator calculate the number of subjects who 
stopped iv BRV and started another AED during the Evaluation Period, the denominator is 
defined as the number of subjects in the FAS from Confirmatory Cohorts.] 
• Proportion of responders to other treatment during the 96-hour Evaluation Period (including 
at the end of the 96-hour Evaluation Period, and by time intervals: 0 hours to 3 hours, >3 
hours to 6 hours, >6 hours to 12 hours, >12 hours to 24 hours, >24 hours to 36 hours, >36 
hours to 48 hours, >48 hours to 72 hours, and >72 hours to 96 hours after the start of initial 
BRV treatment. [Derivations: only subjects who switched from BRV to other treatment 
(stopped BRV due to lack of efficacy) during the 96-hour Evaluation Period will be 
considered for this variable. See the definition of responder to other treatment in 
Section 8.1. The numerator for proportion of responders to other treatment at the end of 96-
hour Evaluation Period is the number of responders to other treatment as defined in 
Section 8.1; the denominator is the number of subjects in FAS from Confirmatory Cohorts.  
The numerator for proportion of responders to other treatment during the time intervals:  0-3 
hours, >3-6 hours, >6-12 hours, >12-24 hours, >24-36 hours, >36-48 hours, >48-72 hours, 
>72-96 hours after the start of initial BRV treatment is defined as the number of responders 
to other treatment with the other treatment stop date and time during 0-3 hours, >3-6 hours, 
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>6-12 hours, …, >48-72 hours, >72-96 hours after the start of initial BRV treatment 
respectively. The denominator is the number of subjects in FAS from Confirmatory Cohorts.] 
8.3.2 
Analysis of other efficacy variables 
Categorical other efficacy variables will be analyzed using descriptive statistics (counts and 
proportions with the 95% CIs). Continuous key efficacy variables will be analyzed descriptively 
as described in Section 3.1. 
A listing of other efficacy variables will be provided for the FAS. 
9 
PHARMACOKINETICS  
The PK data, along with the safety data collected from the Exploratory Cohort and the 3 
Confirmatory Cohorts, will be reviewed by the DMC. In addition, plasma concentrations of BRV 
and its metabolites will be monitored and subjected to interpretation on an ongoing basis. The 
analysis of the PK parameters for the Exploratory and Confirmatory Cohorts will include a sub-
analysis for any concomitant use of hypothermia if allowed by the available data. 
9.1 
Pharmacokinetics 
Pharmacokinetics summary tables and listings will be produced on PK-PPS. Listings of the PK 
parameters and plasma concentrations for all cohorts will be provided.  
9.1.1 
Exploratory Cohort 
Based on the plasma samples collected for the Exploratory Cohort, PK parameters AUC, Cmax, 
t1/2, volume of distribution, and clearance, will be summarized.  
Summary tables will be provided for the PK parameters, for plasma concentrations of BRV, ucb-
42145, ucb-100406-1, ucb-107092-1 and of concomitant AEDs (PB and PHT).   
The same summary tables for subjects with concomitant hypothermia will be provided. 
Individual plots of plasma concentrations over time will be provided. 
9.1.2 
Confirmatory Cohorts 
Based on the plasma samples collected for the Confirmatory Cohorts, PK parameters AUC, Cmax, 
t1/2, volume of distribution, and clearance, will be summarized.  
Summary tables will be provided for the PK parameters, for plasma concentrations of BRV, ucb-
42145, ucb-100406-1, ucb-107092-1 and of concomitant AEDs (PB and PHT) for each 
Confirmatory Cohort separately and overall for combined Confirmatory Cohorts.   
Summary tables for subjects with concomitant hypothermia use will be provided for each 
Confirmatory Cohort separately and overall for combined Confirmatory Cohorts. 
Individual plots of plasma concentrations over time will be provided for each Confirmatory 
Cohort separately and overall for combined Confirmatory Cohorts. 
10 
SAFETY ANALYSES 
All safety analyses will be presented for the SS. Descriptive summaries will be presented overall 
and by cohorts for  
• AEs,  
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• SAEs,  
• physical and neurological examination assessments,  
• laboratory results,  
• vital signs, (SBP, DBP, respiration rate, heart rate, temperature and oxygen saturation) 
• body weight, and  
• head circumference.  
Following subject characteristics related to safety will also be summarized descriptively:  
• cooling status variables (target low body temperature, age since birth when cooling began, 
duration of cooling [date and start and stop time of cooling], and timing of cooling in relation 
to first dose of BRV),  
• rewarming status variables (duration of rewarming [date and start and stop time of 
rewarming] and timing of rewarming in relation to first dose of BRV),  
• the mother’s use of AEDs (including BZD and opiates) at childbirth,  
• N-PASS score, 
• Thompson score,   
• the primary cause of seizure (HIE, hemorrhage, or infarction; CNS malformations; CNS 
infections; undetermined causes), and   
• EEG parameters for the assessment of sedation. 
10.1 
Extent of exposure 
The duration of BRV exposure, is defined as the start date and time of last administration of 
study medication (BRV) minus the start date and time of first administration of study medication 
(BRV) plus duration of dosing interval (12 hours, however the dosing interval may be adjusted if 
results point into that).  
The duration of iv BRV exposure during the Evaluation Period will be displayed in hours. The 
duration of exposure of iv BRV and oral BRV solution during the BRV Extension Period will be 
displayed in days. 
The date and time of last administration of study medication is the maximum date and time from 
the CRFs “Study Medication Administration (Infusion)” and “Study Medication Administration 
(Oral Solution)”.  
Exposure as categorical parameter will be summarized as number of doses received (1 dose, > 1 
dose) and continuous parameter (in hours or days). For the continuous parameter, descriptive 
statistics for the duration of exposure to study medication in hours or days will be presented. For 
the number of doses, the number and percentage of subjects who received 1 dose and >1 doses 
will be summarized. Handling of study medication missing data is described in Section 4.2.4.   
Exposure as a continuous parameter will be categorized (>0-12 hours, >12-24 hours, >24-48 
hours, >48-72 hours, >72-96 hours, >96 hours – 14 days, >14 days) by study periods for 
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Exploratory, individual Confirmatory Cohorts and for overall combined Confirmatory Cohorts 
for the SS. 
The following listings will be provided:   
• study medication administration,  
• exposure to study medication BRV infusion, and  
• exposure to study medication BRV oral solution. 
10.2 
Adverse events 
Treatment-emergent adverse events (TEAEs) are defined as AEs which have onset on or after the 
start date and time of initial study medication (BRV) administration. 
10.2.1 
General summaries of AEs 
A table with overall summary of AEs will be provided separately for Evaluation Period, 
Extension Period, Down-Titration Period, Safety Follow-up Period and for the entire study, the 
table will include:  
− the numbers and percentages of subjects with at least one TEAE  
− the number and percentage of subjects with serious TEAEs  
− the number and percentage of subjects with non-serious TEAEs 
− the number and percentage of subjects with a TEAE that led to permanent 
discontinuation of study medication  
− the number and percentage of subjects with a drug-related TEAE 
− the number and percentage of subjects with a drug-related serious TEAE  
− the number and percentage of subjects with a severe TEAE 
− the number and percentage of subjects with AE leading to death  
− the number and percentage of subjects with TEAEs leading to death 
− the number and percentage of subjects who died prior to the first BRV dose 
The following summary tables of AEs/TEAEs will be provided by primary SOC and PT.  
Summaries will be presented by Exploratory Cohort and individual Confirmatory Cohorts and 
for overall combined Confirmatory Cohorts for the SS.  
• Incidence of pre-treatment AEs  
Pre-treatment AEs are defined as AEs that had onset strictly prior to the date/time of the first 
dose of BRV 
• Incidence of TEAEs (for Evaluation Period, Extension Period, Down-Titration Period, Safety 
Follow-up Period and for the entire study) 
• Incidence of serious TEAEs 
• Incidence of non-serious TEAEs 
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• Incidence of TEAEs by maximum intensity 
Each subject will be counted at most once per primary SOC or PT according to the maximum 
intensity of all AEs within that SOC or PT. Severe intensity will be assumed for AEs for 
which intensity is not specified. 
• Incidence of drug-related TEAEs 
Drug-related AEs are AEs for which the relationship to study medication is specified by the 
Investigator as Related or AEs for which relationship is not specified. 
• Incidence of drug-related serious TEAEs 
Drug-related AEs are AEs for which the relationship to study medication is specified by the 
Investigator as Related or AEs for which relationship is not specified. 
• Incidence of TEAEs by relationship 
• Incidence of non-serious TEAEs by relationship 
• Incidence of serious TEAEs by relationship 
• Incidence of fatal TEAEs by relationship 
• Incidence of TEAEs leading to permanent discontinuation of study medication 
• Incidence of TEAEs leading to death 
• Incidence of non-serious TEAEs above reporting threshold of 5% of subjects in any cohort 
• Incidence of non-serious TEAEs above reporting threshold of 5% of subjects by relationship 
• Incidence of TEAEs of Interest 
Defines as a selection of TEAEs identified by UCB to be of interest to BRV. These are 
identified using an UCB Excel file. 
For the incidence of serious TEAE, TEAEs leading to permanent discontinuation of study 
medication and TEAEs of interest, the summary of subject numbers will be reported. 
Listings AE Glossary and all adverse events will be provided for all subjects screened. 
10.3 
Clinical laboratory evaluations  
10.3.1 
Hematology, Chemistry and Urinalysis Parameters 
Mandatory and optional clinical laboratory parameters are listed in Section 12.1. Continuous 
laboratory variables summary statistics of actual values and change from Baseline will be 
presented by Exploratory Cohort, individual Confirmatory Cohorts and for overall combined 
Confirmatory Cohorts for the SS at each study visit and time point to the end of the Evaluation 
Period.  
The number and percentage of subjects with possibly clinically significant treatment-emergent 
(PCST) value, PCST low values, and PCST high values will be summarized by individual 
Confirmatory Cohorts and for overall combined Confirmatory Cohorts for the SS. The summary 
of subject numbers will be reported as well. PCST criteria are included in the Appendices in the 
Section 12.1. 
The following listings will be provided:  
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• a separate subject data listing for PCST (all laboratory assessments for subjects with PCST 
values are to be included in the listing),  
• all laboratory results of clinical chemistry, hematology and urinalysis laboratory tests. 
 
10.3.2 
Potential Drug Induced Liver Injury 
A summary of the number and percentage of subjects who met PDILI criteria at any point in 
time will be summarized overall, and by cohort for all subjects. Results from local laboratory 
testing should be included, if applicable. Subjects who meet one or more of the criteria for 
potential drug-induced liver injury (PDILI) at any point in time will be listed. The listing will 
display all assessments for which at least one of the criteria for PDILI (see Appendix Error! 
Reference source not found.) was fulfilled for a given subject, and will display all results 
obtained at that time for the specified variables associated with PDILI. Potential Hy’s law cases 
will be flagged.  
All PDILI events require immediate action, testing, and monitoring. The measurements and 
additional information required for the assessment of PDILI events when there is a reasonable 
possibility that they may have been caused by the IMP are included but not limited to those listed 
in laboratory measurements. 
Additional PDILI information will also be listed. If specific PDILI information collected 
separately is matching to the entries in the standard eCRF pages collected for all subjects, the 
specific PDILI information will be added to the corresponding listing for the standard eCRF 
information. For information collected on top (eg, family history of PDILI, lifestyle) a new 
listing will be generated. 
Suspected hepatic events will be listed for the SS. 
10.4 
Vital signs, physical findings, and other observations related to 
safety 
Vital signs SBP (systolic blood pressure), DBP (diastolic blood pressure), respiration rate, 
temperature, oxygen saturation including apnea and heart rate are assessed throughout the study. 
Physical and neurological assessments include Sarnat scale for subjects with HIE, psychometric 
parameter N-PASS, and EEG.   
10.4.1 
Vital signs 
Observed values for SBP, DBP, respiration rate, heart rate, temperature and oxygen saturation 
will be summarized for each visit and time points. Changes from Baseline for SBP, DBP, heart 
rate, respiration rate, temperature, and oxygen saturation will be summarized for post-baseline 
visits and time points. Similar summaries will be provided for body weight.  
Line graph plots of observed vital sign parameters mean values and change from baseline in vital 
sign parameters mean values will be presented by visit and time point. 
The numbers and percentages of subjects with a PCST (possibly clinically significant treatment 
emergent) value, PCST low values, and PCST high value will be summarized for SBP, DBP, 
heart rate, and respiration rate by individual Exploratory Cohort, individual Confirmatory 
Cohorts and for overall combined Confirmatory Cohorts for SS. PCST criteria are based on FDA 
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Division of Neuropharmacologic Drug Products guidelines with some UCB-defined additions 
and are included in the Appendices in the Section 12.1. 
A listing of vital signs will be provided for the SS.  
10.4.2 
Hypothermia treatment 
Listing of hypothermia treatment will be provided for the SS. It will include information if 
subject received hypothermia treatment, age since birth, age since birth when cooling began, 
target low body temperature, date and time cooling began, date and time cooling ended, duration 
of cooling (in days, hours and minutes, date and time cooling ended minus date and time cooling 
started plus 1 minute), timing of cooling in relation to first BRV dose (in hours, relative day and 
time), date and time rewarming began, date and time rewarming ended, duration of rewarming 
(in days, hours and minutes, date and time of end of rewarming minus date and time of start of 
rewarming plus 1 minute) and timing of rewarming in relation to first dose of BRV (in hours, 
date and time of start of rewarming minus date and time of first BRV dose). 
10.4.3 
Mother’s use of AEDs 
A listing of mother’s use of AEDs (including BZDs and/or opiates) with the information on 
mother taking AEDs (BZDs and/or opiates) at the time of delivery, taken medication, dose per 
intake will be provided for the SS. 
10.4.4 
Sarnat scale 
The Sarnat grading scale comprises 6 components: alertness, muscle tone, seizures, pupils, 
respiration, and duration assessed together to provide 3 stages (Grade I [mild]; Grade II 
[moderate]; Grade III [severe]) of HIE. Summaries of shift from Baseline to 24h, 48h, 72h, 96h 
(72h and 96h visits are for Confirmatory Cohorts only) and last value (defined as the latest 
available value) will be provided based on the categories Grade I (Mild), Grade II (Moderate) 
and Grade III (Severe) by individual cohorts and for overall combined Confirmatory Cohorts for 
the SS subjects with HIE. A listing of Sarnat scale will be provided. 
10.4.5 
Thompson score 
Thompson score ranges from 0 to 22 and is calculated by adding the scores from all 9 aspects of 
the neurological examination of infants with HIE. 
Observed values and changes from Baseline in Thompson score will be summarized for post-
baseline visits and time points by individual cohorts and for overall combined Confirmatory 
Cohorts for the SS subjects with HIE. A listing of Thompson score will be provided for the SS. 
10.4.6 
N-PASS scale 
The N-PASS scale was developed as a clinically relevant tool to assess ongoing or acute pain in 
neonates and infants, as well as sedation levels. The 5 indicators are: (1) crying/irritability (silent 
cry observed in the intubated infant is scored as a cry), (2) behavior/state, (3) facial expression, 
(4) extremities/tone, and (5) vital signs. Points are added to the preterm infant’s pain score to 
approximate the normal response of a full-infant.  These points were derived from the Premature 
Infant Pain Profile pain assessment tool (Stevens et al, 1996). Gestational age groups are <28 
weeks (3 points), 28 to 31 weeks (2 points), 32 to 35 weeks (1 point), and >35 weeks (0 points). 
Scores range from 0 to 13. Behavioral state as a modifier was not included in the development of 
N-PASS, as it was designed initially for ongoing pain assessment (Hummel et al, 2010).  
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The N-PASS total Sedation score will be calculated as the sum of negative or zero scores of 
individual indicators (0, -1, -2), the range of sedation score is from 0 to -10. A score of 0 is given 
if the infant has no signs of sedation, does not under-react. Deep sedation is when the score is 
from -10 to -5, light sedation is when the score is from -5 to -2.  
The N-PASS total Pain/Agitation score is calculated as the sum of positive scores of individual 
indicators (1, 2). The total pain score ranges from 0 to 11. Add 1 if gestational age is <30 weeks. 
Observed values and changes from Baseline in N-PASS total sedation and total pain scores will 
be summarized for post-baseline visits and time points by individual cohorts and for overall 
combined Confirmatory Cohorts for SS subjects. 
A listing of N-PASS scores will be provided for the SS. 
10.4.7 
EEG parameters 
A listing of video EEG monitoring (start date and time, stop date and time, was this temporarily 
stopped, interim stop time, reason for temporary stop, restart time, was EEG permanently 
discontinued, reason for discontinuation) for the SS and a listing of reactivity to stimulus on 
vEEG (change of background activity with auditory stimulus, change of background activity 
with painful stimulus) will be provided for the SS. 
10.4.8 
Biometric parameters  
Biometric parameters are body length, body weight and head circumference. Observed values 
and changes from Baseline in biometric parameters will be summarized for post-baseline visits 
and time points by individual cohorts and for overall combined Confirmatory Cohorts for SS 
subjects. A listing of biometric parameters will be provided for the SS. 
10.4.9 
Mechanical ventilation 
Mechanical ventilation variables: 
 − Number and percentage of subjects requiring mechanical ventilation during the Evaluation 
Period [derivations: for subjects from the Exploratory Cohort, the numerator is defined as the 
number of subjects with the mechanical ventilation start date and time after the initial BRV dose 
and no later than 48 hours after the start date and time of the initial BRV dose. For subjects from 
the Confirmatory Cohort, the numerator is defined as the number of subjects with the mechanical 
ventilation start date and time after the initial BRV dose and no later than 96 hours after the start 
date and time of the initial BRV dose, the denominator is defined as the number of subjects in 
the FAS].  
− Duration of mechanical ventilation during the Evaluation Period [derivations: the duration of 
mechanical ventilation during the Evaluation Period is defined if the start date and time of the 
ventilation is after the first BRV dose and not later than 48 hours after the first BRV dose for 
subjects from the Exploratory Cohort and if the start date and time of the mechanical ventilation 
is after the first BRV dose and no later than 96 hours after the first BRV dose for subjects from 
the Confirmatory Cohorts. For subjects from the Exploratory Cohort, the duration is calculated 
as end date and time of the mechanical ventilation minus the start date and time of the ventilation 
if the end date and time of the ventilation is no later than 48 hours after the first BRV dose for 
subjects. If the end date and time of the ventilation is later than 48 hours after the first BRV dose, 
then the duration is calculated as 48 hours minus start date and time of the ventilation. For 
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subjects from the Confirmatory Cohorts, the duration is calculated as end date and time of the 
ventilation minus the start date and time of the ventilation if the end date and time of the 
mechanical ventilation is no later than 96 hours after the first BRV dose. If the end date and time 
of the ventilation is later than 96 hours after the first BRV dose, then the duration is calculated as 
96 hours minus start date and time of the ventilation. The duration is calculated in hours, i.e. the 
number of days is multiplied by 24, then the number of hours added, and the number of minutes 
divided by 60 is added]. 
Summary table will display the number and percentage of subjects requiring mechanical 
ventilation during the Evaluation Period and descriptive statistics for the duration of mechanical 
ventilation during the Evaluation Period. The summary table will be presented by individual 
cohorts and for overall combined Confirmatory Cohorts for SS subjects. 
Listing of mechanical ventilation will be provided for the SS. 
10.4.10 
Bayley-III® score 
Neurodevelopmental tests validated for age and language will be done after 1 year for subjects 
who qualify to enter the long-term follow-up study in countries where a validated translation of 
the Bayley Scales of Infant and Toddler Development ®, Third Edition (Bayley-III®) score is 
available. 
Listing of Bayley-III score will be provided for the SS. 
10.4.11 
Withdrawal and rebound phenomena 
Withdrawal and rebound phenomena will be assessed by observing any AEs experienced by 
subjects following the cessation of BRV administration. These AEs will be reported by the 
Investigators, and any AEs relating to BRV withdrawal will be used for the analysis of 
withdrawal and rebound phenomena. Withdrawal and rebound phenomena, if any, will be 
captured from data collected at the end of BRV exposure for subjects in Confirmatory Cohorts. 
The following summaries will be provided for the SS: incidence of TEAEs with onset during the 
Down-Titration Period, incidence of TEAEs with onset during the Down-Titration Period and 
leading to permanent discontinuation of study medication. 
A listing of AEs with onset during the Down-Titration Period will be provided for the SS. 
10.5 
AED plasma level monitoring 
Listing of AED plasma level monitoring will be provided for the SS. 
10.6 
Drug-Induced Liver Injury (DILI) 
Where applicable, the following listings will be provided for the SS: family medical history for 
suspected DILI cases, hepatic event supplemental medical history, information on potential 
hepato-toxic medications injury, physical examination for DILI, symptoms of hepatitis and 
hypersensitivity, most recent study medication administration for DILI, local laboratory tests for 
DILI and vital signs for DILI. 
 
 
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11 
REFERENCES 
Bayley N. Bayley Scales of Infant and Toddler Development. 3rd ed. San Antonio: Pearson 
Education Inc; 2006. 
Hummel P, Lawlor-Klean P, Weiss MG. Validity and reliability of the N-PASS assessment tool 
with acute pain. J Perinatol. 2010; 30: 474-8. 
Program Conventions Document: Brivaracetam, Version 1.1 (29-Sep-2016) 
Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and 
electroencephalographic study. Arch Neurol. 1976;33:696-705 
Stevens B, Johnston C, Petryshen P, Taddio A. Premature Infant Pain Profile: development and 
initial validation. Clin J Pain. 1996; 12: 13-22. 
Thompson CM, Puterman AS, Linley LL, Hann FM, van der Elst CW, Molteno CD, et al. The 
value of a scoring system for hypoxic ischaemic encephalopathy in predicting 
neurodevelopmental outcome. Acta Paediatr. 1997;86:757-61. 
UCB Global Statistical Conventions, Version 1.1(27-Mar-2014) 
Weeke LC, Toet MC, van Rooij LG, Groenendaal F, Boylan GB, Pressler RM, et al. Lidocaine 
response rate in aEEG-confirmed neonatal seizures: Retrospective study of 413 full-term and 
preterm infants. Epilepsia. 2016; 57(2): 233-42.   
 
 
 
 
 
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12 
APPENDICES 
12.1 
Laboratory Parameters 
Table 12‒1: Mandatory laboratory measurements  
Hematology 
Biochemistry 
Basophils 
Calcium 
Eosinophils 
Chloride 
Lymphocytes 
Potassium 
Atypical lymphocytes 
Sodium 
Monocytes 
Glucose 
Neutrophils 
Urea/BUNa 
Hematocrit 
Creatinineb 
Hemoglobin 
Creatine kinase 
MCH 
AST 
MCHC 
ALT 
MCV 
ALP 
Platelet count 
GGT 
RBC count 
LDH 
WBC count 
Total bilirubin 
 
Direct (conjugated) bilirubin 
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 
a  Urea or BUN to be tested depending on the local lab´s standard panel for neonates. 
b  During the first days of life, creatinine will only be collected if the site assesses this parameter per standard of 
care. 
Table 12‒2: Optional laboratory measurements 
Biochemistry 
Urinalysisb 
Endocrinologyc 
Total cholesterola 
Protein 
TSH 
 
Bacteria 
T4 
 
Glucose 
 
 
pH 
 
 
RBC 
 
 
WBC 
 
RBC=red blood cell; T4=thyroxine; TSH=thyroid-stimulating hormone; WBC=white blood cell 
a Total cholesterol to be measured if this is part of the local lab´s standard panel for neonates. 
b Urinalysis to be performed only if a urine sample was obtained for clinical purposes. A urine dipstick is 
acceptable. 
c TSH and T4 to be recorded for the study only if measured for neonatal screening of congenital hypothyroidism 
prior to or during study participation. 
 
 
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12.2 
Potentially clinically significant treatment-emergent criteria 
(PCST) for neonates (postnatal age up to 1 month) 
Introduction 
This document defines rules to be applied in the safety analyses of the UCB Pharma, Inc. clinical 
development programs in CNS Therapeutic Area.  Rules for detecting possibly clinically 
significant treatment-emergent laboratory values, vital signs, and ECG parameters are 
considered.  The purpose of this document is to bring consistency to reviewing laboratory data 
without over-riding the Investigator’s clinical assessment of these parameters within the clinical 
context of the study subject. 
POSSIBLY CLINICALLY SIGNIFICANT TREATMENT-EMERGENT (PCST) 
CRITERIA 
These possibly clinically significant treatment-emergent (PCST) values are based on grade 2 
toxicity if appropriate grading is available for age group, based on abnormal values or clinical 
experience based on discussion with 
 
 (see comments).   
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12.2.1 
Blood pressure / vital signs  
Parameter low 
high 
Comment 
Heart rate 
<100 
>200 
 
Normal range neonates 85-205 PALS/EPLS1   
Grade 2 is defined as Asymptomatic or symptomatic increase or 
decrease in heart rate, responsive to medical therapy2. Values adapted 
based on discussion with JA. 
Respiration 
rate 
<30 
>60 
 
Normal range neonates 30-60 EPLS1 
Grade 2 is considered persistent tachypnea and/or hypoxemia 
requiring high FiO2 supplementation or CPAP. Associated with other 
clinical symptoms (nasal flaring, grunting, retractions, pallor, or 
cyanosis)2 
Systolic BP 
<40 
mmHg 
>100 
mmHg 
Normal range preterm day 1-7: 48-63 mmHg; term day 1-week 4: 61-
95 mmHg3  
Grade 2 is considered symptomatic and persistent decrease in systolic 
or mean arterial blood pressure ≥15 mm Hg below normal for age 
and gender (symptomatic and persistent increase of >= 35 mmHg 
above normal and gender)2  
Per discussion with JA systolic BP below 48 mmHg may occur in 
preterm infants therefore 40 was chosen.  
Diastolic BP 
<20 
mmHg 
n/a 
 
Normal range preterm day 1-7: 25-35 mmHg; term day 1-week 4: 30-
55 mmHg3  
Per JA diastolic BP <20 would be clinically meaningful. Usually 
clinical decisions in this setting are made based on MAP rather than 
systolic and diastolic pressure 
 
 
 
 
 
                                                 
1Fleming S, Thompson M, Stevens R, et al. Normal ranges of heart rate and respiratory rate in children from birth to 
18 years of age: a systematic review of observational studies. Lancet 2011; published online March 15. 
DOI:10.1016/S0140-6736(10)62226-X.  
  
2 Munoz et al.; Assessment of Safety in Newborns of Mothers Participating in Clinical Trials of Vaccines 
Administered During Pregnancy; Clinical Infectious Disease 2014; Table 1: Recommended core dataset of AE 
definitions and Severity grading  
   
3 Blood pressure disorders - Victorian Agency for Health Information, Safer Care Victoria on  
https://www.bettersafercare.vic.gov.au/resources/clinical-guidance/maternity-and-newborn-clinical-network/blood-
pressure-disorders#goto-normal-neonatal-blood-pressure-values 
 
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12.2.2 
Hematology parameters 
Parameter low 
high 
Comment 
WBC count 
cells/mm3 
≤ 7d: 
<5500 
 
>7d: 
<2000 
>50000 
Grade 2 tox criteria4 
No criteria defined for high WBC; definition based on discussion 
with JA  
Neutrophils 
cells/mm3 
≤ 1d: 
<2000 
 
 
>1d: 
<1000 
n/a 
Grade 2 tox criteria4 
No criteria defined for high neutrophils count 
Adapted based on discussion with JA 
Platelets 
Cells/mm3 
<100.000 
>1000000 
Grade 2 tox criteria4 
No criteria defined for high platelets count; definition based on 
discussion with JA 
Hemoglobin 
g/dL, 
(mmol/L) 
≤ 7d: 
<13 
(<8.05) 
 
8-≤21d: 
<11 
(<6.81) 
 
22-35d: 
<9.5 
(<5.88) 
≤ 7d: > 
16 g/dl 
 
Grade 2 tox criteria4 
No criteria defined for high hemoglobin. DMID criteria are more 
stringent5 
High Hb cutoff added per JA 
 
 
 
 
 
 
 
 
 
                                                 
4 U.S. Department of Health and Human Services, National Institutes of Health, National Institute of Allergy and 
Infectious Diseases, Division of AIDS. Division of AIDS (DAIDS) Table for Grading the Severity of Adult and 
Pediatric Adverse Events, Corrected Version 2.1. [July 2017]. Available from: 
https://rsc.tech-res.com/docs/default-source/safety/division-of-aids-(daids)-table-for-grading-the-severity-of-adult-
and-pediatric-adverse-events-corrected-v-2-1.pdf 
 
5 DIVISION OF MICROBIOLOGY AND INFECTIOUS DISEASES (DMID) PEDIATRIC TOXICITY TABLES 
NOVEMBER 2007 DRAFT 
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12.2.3 
Chemistry (without Bilirubin) 
Parameter 
low 
high 
Comment 
Calcium 
mg/dL 
(mmol/L) 
<7d: 
<6.5 
(<1.63) 
 
>=7d: 
<7.8 
(<1.95) 
<7d: 
>=12.4 
(>=3.1) 
 
>=7d: 
>=11.5 
(>=2.88) 
Grade 2 toxicity based on DAIDS criteria4 
Potassium 
mEq/L 
(mmol/L) 
<3.0 
 
>6.0 
Grade 2 toxicity based on DAIDS criteria4 
Sodium 
mEq/L 
(mmol/L) 
<130 
>=150 
Grade 2 toxicity based on DAIDS criteria4 
Glucose 
mg/dl 
(mmol/L) 
 
<50 
(<2.22) 
>160 
(>13.89) 
Grade 2 toxicity based on DAIDS criteria4 
AST/ALT/ALP 
n/a 
>2.5 ULN 
Grade 2 toxicity based on DAIDS criteria4 
 
12.2.4 
Chemistry (Bilirubin) 
Bilirubin mg/dl 
Postnatal Age 
GA<38 
GA>=38 
Comment 
≤12 h 
6 
8 
Considered PCST if bilirubin values reach cutoff for 
phototherapy recommendation, considering neonates with 
risk factors 
Based on AAP guideline 20046 
 
>12 h and ≤ 24 h 
8 
10 
>24 h and ≤ 48 h 
11 
13 
>48 h and ≤ 72 h 
13 
15 
>72 h and ≤ 96 h 
14 
17 
> 96h 
15 
18 
 
 
                                                 
6 Management of Hyperbilirubinemia in the Newborn Infant 35 or More Weeks of Gestation, AAP, PEDIATRICS 
Vol. 114 No. 1 July 2004 
 
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12.3 
PDILI 
Laboratory value 
ALT or AST 
Total bilirubin 
≥3xULNb 
≥2xULNab 
≥3xULN 
NA 
≥5xULN (and ≥2x baseline) 
<2xULN 
≥3xULN (and ≥2x baseline) and <5xULN 
<2xULN 
a If the subject also has ≥2xULN ALP, the possibility of an indication of biliary obstruction should be discussed 
with the Medical Monitor. 
b The criteria of Hy’s Law are (ALT or AST ≥ 3×ULN) and total bilirubin ≥ 2×ULN. 
 
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13 
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN 
(SAP) 
13.1 
Change from Final SAP 26 April 2018 to SAP Amendment 1 
• List of abbreviations was updated 
• Section 1: updated protocol version 
• Section 2.1 and throughput the rest of the SAP: phenobarbital (PB) was replaced by previous 
antiepileptic drug (AED) 
• Section 2.2: aligned the sub-sections to the protocol to stay consistent between the documents 
• Section 2.2.1: added endpoint Plasma concentrations of BRV on other occasions 
• Section 2.2.2:  
− separate section for main efficacy variable was removed to stay consistent between SAP 
and protocol 
− endpoints were listed and derivation of endpoints were removed from this section 
• Section 0: section was aligned with protocol to define secondary safety variable (AE) and list 
other safety variables 
• Section 2.3:  
− The sentence “N01349 consists of 2 steps including a comparison with a historical 
control from literature (midazolam (MDZ) treatment from literature of subjects matched 
in age and condition) for the evaluation of efficacy.” was replaced by “N01349 consists 
of a 2-step design and includes a descriptive comparison with a historical control group 
(matched in age and condition) from literature treated with AEDs per System Organ 
Class (SOC) and diagnostic methods.” 
− “multiple therapeutic doses of MDZ” was replaced by “AEDs for the treatment of ENS 
per SOC (first-line, second-line, or subsequent treatment; choice of treatment “. 
− Reference “N01266” as long term study was removed to use a more general wording 
• Section 2.3.1 and Section 2.3.2 : Specified information about study periods and cohorts, and 
reworded for clarification according to protocol amendments. 
• Section 2.3.3: Specified periods for the Confirmatory Cohorts 
• Section 2.4:  
− Removed “MZD treated” 
− Specified that only subject from Confirmatory Cohort who drop out or withdrawal will 
not be replaced. 
• Section 3.1: 25th and 75th percentile were removed from standard descriptive statistics as 
there are not foreseen in the standard mock shells. 
• Section 3.2.1.2: Corrected typo of “mediation” to “medication” 
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• Section 3.2.2: Removed all repeated texts from Section 2.3 and defined start and end of each 
study period for Exploratory Cohort and Confirmatory Cohorts. 
• Section 3.2.4: Section added to describe who is classified as completing the study. 
• Section 3.3: Sentence “Assessments taken on the date of study medication administration 
without a reported time will not be considered for baseline assessments (eg, will be assumed 
to have been taken after the start time of study medication administration)” was removed as 
this could lead to missing baseline value. 
• Section 3.5: Abbreviations were used 
• Section 3.6: Enrolled Set was removed as it is not defined in the protocol. 
• Section 4.2.5: Section added to describe potential impact of COVID-19 on this study and, 
how information about this will be captured and used. 
• Section 4.3: aligned the DMC meeting occurrence to the DMC Charter to stay consistent 
between the documents. 
• Section 5.2:  
− Main categories of protocol deviations were added. 
− Listing of subjects excluded from FAS will not be needed and is removed. Only subject 
listing excluded from PK-PPS Set will be provided. 
− Information added to describe how subjects with a completed COVID-19 Impact eCRF 
page will be assessed, and displayed 
• Section 6.1:  
− Clarified that demographic variables will be presented for FAS, PK-PPS and SS overall 
and by cohorts. 
− "Gestational age (weeks)” was replaced by “Corrected gestational age”. 
− “Postnatal age” was added 
− “HIE status” was added. 
• Section 6.2: Listings will be provided for SS instead of ES, which was removed as not 
defined in protocol. 
• Section 6.4.2: Sentence “In the event of ambiguity or incomplete data which makes it 
impossible to determine whether a medication was concomitant or not, the medication will be 
considered as concomitant” added for clarity. 
• Section 6.4.3, 6.4.4, 6.4.5 and 6.4.6: Subject data listings were added. 
• Section 7.1: It was specified that listing for oral solution will be provided during the BRV 
Extension Period for the SS. 
• Section 8: 
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− Sentence “Seizure efficacy data may also be transformed if needed. The transformation 
of seizure data to be used (if needed) will be log (x + 1) where x is the neonate seizure 
count or the seizure burden” was added for clarification. 
− Section was reordered to have first the endpoint definition and derivation and then 
section for analysis. 
− Added subsection titles for each definition of endpoints. 
• Section  8.1.1 Reworded for clarification. 
• Section 8.1.2 Added subsection to explain difference between non-severe and severe baseline 
seizure burden and derivation of seizure burden. 
• Section 8.2: Renamed section to “Statistical analysis of the secondary efficacy variables” to 
stay align with protocol. 
• Section 8.2.1, 8.2.2, 8.2.3 and 8.2.5: Added “secondary” to section titles for clarification. 
• Section 8.2.4:  
− Title changed from “Statistical analysis of the key efficacy variables” to “Derivations of 
the secondary efficacy variables”. 
− Absolute and percentage reduction in absolute seizure burden were split into two 
passages. 
− Absolute and percent difference in clinical seizures were split into two passages. 
• Section 8.2.5 and 8.3.2: FAS analysis set was added to the listing. 
• Section 10:  
− SBP, DBP, respiration rate, pulse rate, temperature and oxygen saturation were added to 
the vital signs. 
− Updated wording for clarification. 
• Section 10.1  
− Added “start” to clarify that the start date and time of administration is used for exposure 
calculation. 
− Removed “Multiply the number of days by 24, add number of hours and number of 
minutes divided by 60” as this will be not needed. 
• Section 10.2: Replaced “Treatment-emergent adverse events (TEAEs) are defined as AEs 
which have onset on or after the start date and time of study medication administration” with 
“Treatment-emergent adverse events (TEAEs) are defined as AEs which have onset on or 
after the start date and time of initial study medication (BRV) administration” for 
clarification. 
• Section 10.2.1:  
− Extension and Safety Follow-up Period was added for Incidence of TEAE by period. 
− Summary for Incidence of TEAEs leading to death was added. 
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• Section 10.3: Added “Mandatory and optional clinical laboratory parameters are listed in 
Section 12.1” for clarification. 
• Section 10.3.2 Potential Drug Induced Liver Injury was added. 
• Section 10.4.2, 10.4.5, 10.4.6, 10.4.7, 10.4.8, 10.4.9 and 10.4.11: Added SS analysis set for 
listing of hypothermia treatment, listing of Thomson score, listing of N-PASS scores, listing 
of EEG parameters, listing of biometric parameters, listings of mechanical ventilation and for 
the summaries and listings of withdrawal and rebound phenomena. 
• Section 12.1: Laboratory parameters were added. 
• Section 12.2.1: Pulse rate was replaced by heart rate to stay consistent throughout the 
document. 
• Section 12.3: PDILI was added. 
• Section 13: Changes to the final SAP 16 April 2018 were added. 
 
 
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13.2 
Change from SAP Amendment 1 to SAP Amendment 2 
• List of abbreviations was updated 
• Section 2.2.3.2 and throughput the rest of the SAP: pulse rate was removed 
• Section 3.2.1.1: Clarified how the relative day and time will be displayed in listings 
• Section 3.3: Section added to describe the relationship among three age indicators and, how 
each indicator will be calculated. 
• Section 3.4: It was specified that if baseline assessment of biometric parameters (length, 
weight, head circumference) is taken on the same day as first dose of BRV infusion and 
assessment time is not known, the latest value at Screening or Baseline visit before or on the 
date of first dose of BRV infusion will be utilized as Baseline value. 
• Section 5.1: Clarified what summary will be presented for subjects who discontinued this 
study due to AEs. 
• Section 6.1: Some demographic variables were added. 
• Section 6.4: 
- 
Specified file to be used to identify of non-AED or AED medications. 
- 
Added paragraph to describe the grouping of similar AED medications. 
• Section 6.4.2: “In the event of ambiguity or incomplete data which makes it impossible to 
determine whether a medication was concomitant or not, the medication will be considered 
as concomitant.” was removed. 
• Section 7.2: Updated the definition of treatment noncompliance. 
• Section 8.1.2: Removed explanation of how the number of severe and non-severe seizures 
are standardized. 
• Section 8.1.4: Updated wording for clarification how average per hour seizure burden will be 
calculated 
• Section 10.1: Clarified that only duration of iv BRV exposure during the Evaluation Period 
will be displayed in hours. 
• Section 10.2.1:  
- 
Added the definition of pre-treatment AEs. 
- 
“the number and percentage of subjects who death prior to the first BRV dose” variable 
was added 
• Section 10.4.1:  
- 
Removed “Change from baseline in heart rate at 3 hours, 24 hours, 48 hours and 96 hours 
after the start of initial BRV treatment will be summarized.” as this will be not needed. 
- 
Added clarification for vital sign PCST summary. 
• Section 10.4.2: Calculation of the duration of cooling and rewarming was clarified. 
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• Section 10.4.9: Added descriptive statistics for the duration of mechanical ventilation. 
• Section 10.5: Section added to describe the output that must be provided. 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution. 
 
 
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Approval Signatures
Name:
n01349-sap-amend-2
Version:
1. 0
Document Number:
CLIN-000173752
Title:
N01349 - Statistical Analysis Plan
Amendment # 2
Approved Date:
18 May 2021
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 13-May-2021 11:27:24 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 17-May-2021 22:25:08 GMT+0000
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