A Multicenter, Open-Label, Randomized, Active Comparator Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Lacosamide in Neonates With Repeated Electroencephalographic Neonatal Seizures
Phase: PHASE2
Conditions: Electroencephalographic Neonatal Seizures, Epilepsy
Sponsor: UCB Biopharma SRL

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Clinical Study Protocol 
Lacosamide 
SP0968 
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A MULTICENTER, OPEN-LABEL, RANDOMIZED, ACTIVE 
COMPARATOR STUDY TO EVALUATE THE EFFICACY, 
SAFETY, AND PHARMACOKINETICS OF LACOSAMIDE IN 
NEONATES WITH REPEATED 
ELECTROENCEPHALOGRAPHIC NEONATAL SEIZURES 
PROTOCOL SP0968 AMENDMENT 2 
PHASE 2/3 
Short title: 
Study of lacosamide in neonatal seizures 
Sponsor: 
UCB Biopharma SRL 
Allée de la Recherche 60 
1070 Brussels 
BELGIUM 
Regulatory agency identifying number(s): 
Eudra CT Number: 
2020-001066-10 
IND Number: 
068407 (intravenous) 
073809 (oral solution) 
NCT Number 
NCT04519645 
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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PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE 
Document History 
Document 
Date 
Type of amendment 
Amendment 2  
11 Feb 2022 
Substantial  
Amendment 1 
13 Oct 2020 
Substantial 
Original Protocol 
25 Mar 2020 
Not applicable 
Amendment 2 (11 Feb 2022) 
Overall Rationale for the Amendment 
Changes to the protocol have been made to align the study more closely with the Neonatal 
Intensive Care Unit’s (NICU) standard of care and practice, clarify the age criterion, clarify the 
Schedule of Activities, align with the current Statistical Analysis Plan (SAP), and align with the 
current lacosamide (LCM) clinical development program. Minor grammatical, editorial, and 
formatting changes have also been made for clarification purposes only. 
Section # and Name 
Description of Change 
Brief Rationale 
1.3 Schedule of Activities 
4.1.2 Study periods 
Update Baseline Period within 
the Screening Period 
from -1 hour to 0 hour 
to -2 hours to 0 hour. 
To align the study more closely 
with NICU’s standard of care 
and practice. 
1.1 Synopsis 
1.2 Schema 
1.3 Schedule of Activities 
4.1.1 Video-EEG 
5.1 Inclusion criteria  
8.1.1.1 Assessment of seizure 
burden 
Update to reflect the increase in 
the duration of the Baseline 
video-EEG recording period 
from 1 hour to 2 hours. Specify 
that the occurrence of ENS is to 
occur during an up to 2-hour 
period, with at least 30 seconds 
of cumulative ENS in an hour. 
To align the study more closely 
with NICU’s standard of care 
and practice. 
1.3 Schedule of Activities 
Reduce the number of ECG 
assessments to 4 timepoints 
within the Screening and 
Treatment Period: Screening or 
Baseline (-24h to 0h), postdose 
(1-6h), at 48h, and at 96h. 
Clarify footnote to specify that 
the ECG postdose 1-6h is 
preferred to be taken as close to 
the first hour as possible. 
To align the study more closely 
with NICU’s standard of care 
and practice. 
1.1 Synopsis 
2.1 Study rationale 
4.2 Scientific rationale for study 
design  
5.1 Inclusion criteria  
Update inclusion criteria for age 
from gestational age to 
corrected gestational age 
(CGA), clarify CGA weeks, and 
To clarify the age criterion and 
slightly broaden the potential 
patient population. 
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remove postmenstrual age 
requirement.  
5.2 Exclusion criteria 
Replace exclusion criteria 
creatinine clearance measured 
by Schwartz formula with: if 
participant is in the first 24 
hours of life, urine output is 
<1mL/kg/hour. If older than 
24 hours, participant urine 
output is <1mL/kg/hour or 
serum creatinine >1.7mg/dL. 
To align the study more closely 
with NICU’s standard of care 
and practice. 
1.3 Schedule of Activities  
Clarify with a footnote that 
Treatment Period dosing will be 
up to the 96 hour timepoint; 
however, at 96 hours the study 
participant may enter the 
Extension period and receive 
LCM either as oral solution or 
iv infusion.  
The Schedule of Activities 
indicates that LCM infusion 
occurs at 96 hours; however, 
study participants are given the 
option to receive oral solution or 
iv infusion at the 96 hour 
timepoint; therefore, the mark is 
footnoted to clarify.  
1.3 Schedule of Activities 
Mark the following assessment: 
physical and neurological 
examinations, for conduct at 48 
hours of the Treatment Period. 
The Schedule of Activities did 
not indicate physical and 
neurological examination at 
48 hours of the Treatment Period. 
For consistency with the “Other 
Endpoints” whereby change from 
Baseline in physical and 
neurological examinations is 
conducted at 24 hours, 48 hours, 
72 hours, and 96 hours, the 
assessment is marked at 48 hours 
in the Schedule of Activities.  
Section 6.3 Measures to 
minimize bias: Randomization 
Section 9.1 Definition of 
analysis sets 
9.4 Planned safety analyses 
Section 9.9 Determination of 
sample size 
Section 11 References 
Global updates to align protocol 
with the SAP including 
alignment of analysis sets and 
determination of sample size 
text. 
To align with the current SAP for 
accuracy in the protocol. 
1.1 Synopsis 
2.1 Study Rationale  
2.2 Background 
2.2.1 LCM in pediatric studies 
2.3 Benefit/Risk Assessment 
Global updates of study status 
and approvals of LCM since last 
protocol amendment.  
To align with the current LCM 
clinical development program. 
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SERIOUS ADVERSE EVENT REPORTING 
Serious adverse event reporting (24h) 
Fax 
All regions: +32 238 66561  
Email 
Global: PSRapidalert@ucb.com  
 
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TABLE OF CONTENTS 
1 
PROTOCOL SUMMARY ................................................................................................. 9 
1.1 
Synopsis ......................................................................................................................... 9 
1.2 
Schema ......................................................................................................................... 13 
1.3 
Schedule of Activities .................................................................................................. 16 
2 
INTRODUCTION ........................................................................................................... 22 
2.1 
Study Rationale ............................................................................................................ 23 
2.2 
Background .................................................................................................................. 23 
2.2.1 
LCM in pediatric studies ..................................................................................... 24 
2.3 
Benefit/Risk Assessment ............................................................................................. 25 
3 
OBJECTIVES AND ENDPOINTS ................................................................................. 27 
4 
STUDY DESIGN ............................................................................................................. 28 
4.1 
Overall design .............................................................................................................. 28 
4.1.1 
Video-EEG .......................................................................................................... 29 
4.1.2 
Study periods ....................................................................................................... 29 
4.2 
Scientific rationale for study design ............................................................................ 31 
4.3 
Justification for dose .................................................................................................... 32 
4.4 
End of study definition................................................................................................. 33 
5 
STUDY POPULATION .................................................................................................. 33 
5.1 
Inclusion criteria .......................................................................................................... 33 
5.2 
Exclusion criteria ......................................................................................................... 34 
5.3 
Lifestyle restrictions..................................................................................................... 35 
5.4 
Screen failures .............................................................................................................. 35 
6 
STUDY TREATMENTS ................................................................................................. 36 
6.1 
Treatments administered .............................................................................................. 36 
6.2 
Preparation, handling, storage, and accountability requirements ................................ 36 
6.2.1 
Drug accountability ............................................................................................. 37 
6.3 
Measures to minimize bias: Randomization ................................................................ 37 
6.3.1 
Procedures for maintaining and breaking the treatment blind ............................. 37 
6.4 
Treatment compliance .................................................................................................. 37 
6.5 
Concomitant medication(s)/treatment(s) ..................................................................... 38 
6.5.1 
Permitted concomitant treatments (medications and therapies) .......................... 38 
6.5.2 
Prohibited concomitant treatments (medications and therapies) ......................... 38 
6.5.3 
Rescue medication ............................................................................................... 38 
6.6 
Dose modification ........................................................................................................ 38 
6.7 
Criteria for study hold or dosing stoppage ................................................................... 39 
6.8 
Treatment after the end of the study ............................................................................ 39 
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7 
DISCONTINUATION OF STUDY MEDICATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ........................................................................ 39 
7.1 
Discontinuation of study medication ........................................................................... 39 
7.1.1 
Liver stopping criteria - potential drug-induced liver injury ............................... 39 
7.1.2 
ECG stopping criteria .......................................................................................... 40 
7.1.3 
Temporary discontinuation .................................................................................. 40 
7.1.4 
Rechallenge .......................................................................................................... 40 
7.2 
Participant discontinuation/withdrawal from the study ............................................... 40 
7.3 
Lost to follow up .......................................................................................................... 41 
8 
STUDY ASSESSMENTS AND PROCEDURES ........................................................... 41 
8.1 
Efficacy assessments .................................................................................................... 42 
8.1.1 
Assessments of primary efficacy endpoints ........................................................ 42 
8.1.1.1 
Assessment of seizure burden ................................................................... 42 
8.1.1.2 
Assessment of responder ........................................................................... 42 
8.2 
Safety assessments ....................................................................................................... 43 
8.2.1 
Medical history including Apgar score ................................................................ 43 
8.2.2 
Vital signs ............................................................................................................ 43 
8.2.3 
Physical and neurological examinations .............................................................. 43 
8.2.3.1 
Sarnat score ............................................................................................... 43 
8.2.4 
Biometric parameters ........................................................................................... 43 
8.2.5 
Electrocardiograms .............................................................................................. 44 
8.2.6 
Total blood collected ........................................................................................... 44 
8.2.7 
Clinical safety laboratory assessments ................................................................ 44 
8.3 
Adverse events and serious adverse events ................................................................. 44 
8.3.1 
Time period and frequency for collecting AE and SAE information .................. 45 
8.3.2 
Method of detecting AEs and SAEs .................................................................... 45 
8.3.3 
Follow up of AEs and SAEs ................................................................................ 45 
8.3.4 
Regulatory reporting requirements for SAEs ...................................................... 45 
8.3.4.1 
Immediate reporting of AEs ...................................................................... 46 
8.3.5 
Adverse events of special interest ........................................................................ 46 
8.4 
Safety signal detection ................................................................................................. 47 
8.5 
Treatment of overdose ................................................................................................. 47 
8.6 
Pharmacokinetics ......................................................................................................... 48 
8.6.1 
Pharmacokinetic sampling and handling ............................................................. 48 
8.6.2 
Pharmacokinetic sample shipment ...................................................................... 48 
8.6.3 
Pharmacokinetic analysis ..................................................................................... 48 
8.7 
Genetics........................................................................................................................ 48 
8.8 
Pharmacodynamics ...................................................................................................... 48 
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8.9 
Biomarkers ................................................................................................................... 48 
9 
STATISTICAL CONSIDERATIONS ............................................................................. 49 
9.1 
Definition of analysis sets ............................................................................................ 49 
9.2 
General statistical considerations ................................................................................. 49 
9.3 
Planned efficacy analyses ............................................................................................ 49 
9.3.1 
Analysis of the primary efficacy endpoint ........................................................... 49 
9.3.2 
Analysis of the secondary efficacy endpoints ..................................................... 50 
9.3.2.1 
Time to response ....................................................................................... 50 
9.3.2.2 
Time to seizure freedom ............................................................................ 50 
9.4 
Planned safety analyses................................................................................................ 51 
9.5 
Planned pharmacokinetics analyses ............................................................................. 51 
9.6 
Handling of protocol deviations................................................................................... 51 
9.7 
Handling of dropouts or missing data .......................................................................... 51 
9.8 
Planned interim analysis and data monitoring ............................................................. 51 
9.8.1 
Definition of stopping rules ................................................................................. 51 
9.9 
Determination of sample size ....................................................................................... 52 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS... 52 
10.1 
Appendix 1: Regulatory, ethical, and study oversight considerations ......................... 52 
10.1.1 
Regulatory and ethical considerations ................................................................. 52 
10.1.2 
Financial disclosure ............................................................................................. 53 
10.1.3 
Informed consent process .................................................................................... 53 
10.1.4 
Data protection ..................................................................................................... 54 
10.1.5 
Data quality assurance ......................................................................................... 54 
10.1.5.1 
Case Report form completion .................................................................... 55 
10.1.5.2 
Apps ........................................................................................................... 55 
10.1.6 
Source documents ................................................................................................ 55 
10.1.7 
Study and site closure .......................................................................................... 56 
10.1.8 
Publication policy ................................................................................................ 56 
10.2 
Appendix 2: Clinical laboratory tests .......................................................................... 57 
10.3 
Appendix 3: Adverse events – Definitions and procedures for recording, evaluating, 
follow up, and reporting ............................................................................................... 58 
10.4 
Appendix 4: Contraceptive guidance and collection of pregnancy information ......... 62 
10.5 
Appendix 5: Genetics ................................................................................................... 63 
10.6 
Appendix 6: Liver safety – Suggested actions and follow-up assessments ................. 64 
10.7 
Appendix 7: Medical device adverse events, adverse device effects, serious adverse 
events and device deficiencies: definition and procedures for recording, evaluating, 
follow up, and reporting ............................................................................................... 67 
10.8 
Appendix 8: Rapid alert procedures ............................................................................ 68 
10.9 
Appendix 9: Country-specific requirements ................................................................ 69 
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10.10 Appendix 10: Abbreviations and trademarks .............................................................. 70 
10.11 Appendix 11: Protocol amendment history ................................................................. 72 
11 REFERENCES ................................................................................................................ 76 
SPONSOR DECLARATION .................................................................................................. 79 
 
LIST OF TABLES 
Table 1-1: 
Schedule of Activities – Screening and Treatment Periods ............................. 17 
Table 1-2: 
Schedule of Activities - Extension and Safety Follow-up Periods .................. 20 
Table 1-3: 
Schedule for PK sampling ............................................................................... 21 
Table 2-1: 
Overview of ongoing and completed studies of LCM in partial-onset 
seizures that include study participants <17 years of age ................................ 24 
Table 6-1: 
Treatments administered .................................................................................. 36 
Table 9‒1: 
Example of assumed responses for the two treatment groups and 
treatment effects using different metrics.......................................................... 52 
 
LIST OF FIGURES 
Figure 1-1: 
Schematic overview of the study ..................................................................... 14 
 
 
 
 
 
 
 
 
 
 
 
 
 
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1 
PROTOCOL SUMMARY 
1.1 
Synopsis 
Protocol title: 
A multicenter, open-label, randomized, active comparator study to evaluate the efficacy, safety, 
and pharmacokinetics of lacosamide in neonates with repeated electroencephalographic neonatal 
seizures 
Short Title: 
Study of lacosamide in neonatal seizures 
Rationale: 
Seizures occur more often during the neonatal period than at any other time during life, the most 
common cause being hypoxic-ischemic encephalopathy (HIE) as a result of perinatal asphyxia. 
The current accepted medical practice for neonatal seizures is initial treatment with 
first-generation anti-epileptic drugs (AEDs) such as phenobarbital (PB) and phenytoin (PHT) 
with rapid progression to treatment with midazolam (MDZ) for patients without adequate seizure 
control after 2 doses of PB. Recently, levetiracetam (LEV) is being used more often as first-line 
and second-line treatment. In up to 50% of patients, 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. 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. There is a need to investigate which 
AEDs should be used to treat neonatal seizures and their most appropriate dosages. 
Lacosamide (LCM) is approved for treatment of partial-onset seizures for patients ≥4 years of 
age in the European Union and down to ≥1 month of age in the United States. A study of safety 
and tolerability of the intravenous (iv) formulation of LCM (EP0060) has recently been 
completed in pediatric study participants with epilepsy down to the age of 1 month with an 
infusion duration of 15 to 60 minutes. The efficacy of LCM was evaluated for partial-onset 
seizures in participants ≥1 month to <4 years of age (SP0967). 
SP0968 represents the first clinical study of LCM in neonatal study participants and is designed 
for the flexible treatment of electroencephalographic neonatal seizures (ENS). This study will 
evaluate the efficacy, safety, and pharmacokinetics (PK) of LCM in neonates (≥34 weeks of 
corrected gestational age [CGA], <46 weeks of CGA, and <28 days of postnatal age [PNA]). 
Lacosamide will be evaluated against an Active Comparator chosen based on the standard of 
care (StOC) per the local practice and treatment guidelines. Only those participants who do not 
have adequate seizure control with previous AED treatment (PB, LEV, or MDZ in any 
combination; additional benzodiazepines [BZDs] are allowed) will be permitted to enroll in 
SP0968. 
 
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Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
• 
To evaluate the efficacy of LCM vs an 
Active Comparator chosen based on StOC 
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 
• 
Reduction in seizure burden measured in the 
Evaluation a video-EEG compared with the 
Baseline video-EEG 
Secondary 
• 
To further evaluate the efficacy of LCM vs 
an Active Comparator 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 
• 
Proportion of responders in the Evaluation a 
video-EEG compared with the Baseline 
video-EEG 
• 
Proportion of participants with at least 80% 
reduction in seizure burden in the Evaluation a 
video-EEG compared with the Baseline 
video-EEG 
• 
Time to response across the first 48-hours of the 
Treatment Period compared with the Baseline 
video-EEG 
• 
Time to seizure freedom across the first 48-hours 
of the Treatment Period compared with the 
Baseline video-EEG 
• 
Absolute reduction in seizure burden across the 
first 48-hours of the Treatment Period measured 
by continuous video-EEG compared with the 
Baseline video-EEG 
• 
Percent reduction in seizure burden across the 
first 48-hours of the Treatment Period measured 
by continuous video-EEG compared with the 
Baseline video-EEG 
• 
Proportion of responders at the end of the first 
48-hours of the Treatment Period 
• 
Proportion of study participants who are seizure-
free (100% reduction in seizure burden from 
Baseline) at 24 hours after the start of the 
Treatment Period, categorized by study 
participants with nonsevere or severe seizure 
burden at Baseline 
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Objectives 
Endpoints 
• 
Categorized percentage reduction in seizure 
burden in the Evaluation a video-EEG compared 
with the Baseline video-EEG (<-25% 
[worsening], -25% to <25% [no change], 25% to 
<50%, 50% to <80%, and ≥80%) 
• 
To evaluate the short-term safety and 
tolerability of LCM in neonates 
• 
TEAEs as reported by the investigator 
• 
Percentage of treatment-emergent marked 
abnormalities b in 12-lead ECG 
• 
To evaluate the PK of LCM in neonates 
who have seizures that are not adequately 
controlled with previous AED treatment 
• 
Mean serum concentration of LCM 
Other 
• 
To further evaluate the short-term safety 
and tolerability of LCM in neonates 
• 
Percentage of treatment-emergent marked 
abnormalities b in hematology and chemistry 
parameters 
• 
Percentage of treatment-emergent marked 
abnormalities b in vital sign measurements (ie, 
BP and pulse rate) 
• 
Change from Baseline in physical and 
neurological examinations at 24 hours, 48 hours, 
72 hours, and 96 hours after the start of initial 
treatment 
AED=anti-epileptic drug; BP=blood pressure; ECG=electrocardiogram; ENS=electroencephalographic neonatal 
seizures; LCM=lacosamide; PK=pharmacokinetics; StOC=standard of care; TEAE=treatment-emergent adverse 
event; video-EEG=video-electroencephalogram 
a The 2-hour evaluation for efficacy will start 1 hour after initiation of randomized treatment (LCM or Active 
Comparator) and will be used for evaluation of the primary endpoint based on video-EEG. 
b Marked abnormalities will be defined in the Statistical Analysis Plan. 
Overall Design 
This is a Phase 2/3, multicenter, open-label, randomized, active comparator study to evaluate the 
efficacy, safety, and PK of LCM in neonates with repeated ENS compared with an Active 
Comparator chosen based on StOC per the local practice and treatment guidelines. 
Study participants who have confirmation on video-electroencephalogram (video-EEG) of 
≥2 minutes of cumulative ENS or ≥3 identifiable ENS prior to entering the Treatment Period 
(ENS is defined as a seizure lasting for at least 10 seconds on video-EEG), despite receiving 
previous AED treatment (PB, LEV, or MDZ in any combination; additional BZDs are allowed) 
will be enrolled in the study. Participants must be ≥34 weeks of CGA, <46 weeks of CGA, and 
<28 days of PNA at the time of signing the informed consent. 
The study involves Screening Period of up to 36 hours followed by a 96-hour Treatment Period 
during which study participants will be randomized 1:1 and stratified by seizure severity to 
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receive either LCM or an Active Comparator. The Active Comparator treatment will be chosen 
and dosed based on StOC (per local practice and treatment guidelines). The video-EEG 
recording needs to have started at least 2 hours before treatment randomization and will continue 
for 48 hours after administration of the first dose of randomized treatment (LCM or Active 
Comparator). The 2-hour evaluation for efficacy will start 1 hour after initiation of randomized 
treatment and will be used for evaluation of the primary endpoint based on video-EEG. Rescue 
medication, if needed, can be administered during the Treatment Period. Ideally, rescue 
medication will not be given within the first 3 hours of randomized treatment; however, the 
administration of rescue medication is always at the discretion of the investigator. At the end of 
the Treatment Period, study participants may continue to receive randomized treatment in the 
Extension Period. Study participants who discontinue randomized treatment during the 
Treatment Period or the Extension Period will enter the Safety Follow-up (SFU) Period. During 
the SFU Period, study participants randomized to LCM will have the option of down titrating 
their LCM dose. 
A 1:1 (LCM:Active Comparator) randomization scheme will be used for the treatment allocation 
to participants in the study. Randomization will occur after completion of the End-of-Baseline 
video-EEG (at least 30 minutes) and after confirmation that the participant has met eligibility 
criteria. The randomization will be stratified by seizure severity (as defined in Section 8.1.1.1). 
Number of Participants 
A total of 32 study participants are planned to be enrolled. 
Treatment Groups and Duration 
The total duration of the study for an individual study participant is a maximum of 42 days and 
will include the following periods: 
• Screening Period: up to 36 hours (-36 hour to 0 hour) 
• Treatment Period: 96 hours (0 hour to 96 hour) 
• Extension Period: up to 28 days of PNA 
• Safety Follow-up Period (with optional down titration): 14 days 
During the Treatment Period, study participants will be randomized to either the LCM or Active 
Comparator (StOC, based on local practice and treatment guidelines) treatment group. Study 
participants randomized to LCM will receive an iv infusion of LCM over 30 minutes. A dose of 
LCM 15mg/kg/day is estimated to yield approximately the same plasma concentrations as in an 
adult receiving LCM 400mg/day. The planned LCM dose in the study may be adjusted during 
the study as more PK information in neonates is obtained from ongoing studies and as SP0968 
progresses. The sponsor will review the interim safety and PK data and inform the investigators 
if a dose modification is needed. The actual LCM dose during the study for each study 
participant will be provided by Interactive Response Technology (IRT). Study participants 
randomized to Active Comparator will receive an Active Comparator treatment chosen and 
dosed based on StOC (per local practice and treatment guidelines). 
Following the Treatment Period, all study participants who remain inpatient and continue to 
receive the randomized treatment (LCM or Active Comparator) will enter the Extension Period. 
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Study participants in the LCM group may continue receiving the same LCM dose administered 
at the end of the Treatment Period; the LCM dose should not be increased, but may be decreased, 
at the discretion of the investigator. Participants on LCM should be switched to oral dosing of 
LCM as soon as medically possible during the Extension Period. 
Study participants who discontinue randomized treatment at any time (Treatment or Extension 
Period), complete the Extension Period, are discharged from the hospital or reach 28 days PNA, 
will enter the 14-day SFU Period. During the SFU Period, participants on LCM have the option 
of down titrating their LCM dose over 7 days; it is recommended that the LCM dose be tapered 
gradually in daily decrements of 3mg/kg/day. Study participants will return to the site for the 
SFU visit at the end of the 14-day SFU period. 
1.2 
Schema 
A schematic overview of the study design is presented in Figure 1-1. 
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Figure 1-1: Schematic overview of the study 
 
AED=anti-epileptic drug; BDZ=benzodiazepine; d=day; ENS= electroencephalographic neonatal seizures; h=hour; IRT=Interactive Response Technology; 
iv=intravenous; LCM=lacosamide; LEV=levetiracetam; MDZ=midazolam; PB=phenobarbital; PNA=postnatal age; SFU=Safety Follow-up; StOC=standard of 
care; video-EEG=video-electroencephalogram 
a Study participants eligible based on Baseline video-EEG seizure burden and other inclusion and exclusion criteria will be randomized to the LCM or Active 
Comparator treatment group. 
b Study participants randomized to LCM will receive an iv infusion of LCM over 30 minutes, 3 times a day. The actual LCM dose during the study for each 
study participant will be provided by IRT. 
c Study participants randomized to Active Comparator will receive an Active Comparator treatment chosen and dosed based on StOC (per local practice and 
treatment guidelines). 
d Study participants must have been administered LEV, PB, or MDZ (in any combination) for treatment of ENS prior to enrollment. Other BDZ may have been 
given additionally. Sodium channel blockers (such as phenytoin or lidocaine) are not permitted prior to enrollment but are permitted in the Active Comparator 
treatment group (ie, the Active Comparator may be a sodium channel blocker). 
e Video-EEG recording can be shortened per clinical need (eg, if status epilepticus is detected). If possible, an attempt should be made to record at least 
30 minutes of Baseline video-EEG. 
f Evaluation for efficacy will start 1 hour after initiation of randomized treatment (LCM or Active Comparator) and will be used for assessment of the primary 
endpoint based on video-EEG. 
g Ideally, rescue medication will not be given within the first 3 hours of randomized treatment; however, the administration of rescue medication is always at the 
discretion of the investigator. 
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h Study participants who benefit from randomized treatment (LCM or Active Comparator) can continue to the Extension Period. Study participants who 
discontinue randomized treatment at any time (Treatment or Extension Period), complete the Extension Period, are discharged from the hospital, or reach 
28 days PNA, will enter the 14-day SFU Period with optional down titration. Study participants will return to the site for the SFU visit at the end of the 14-day 
SFU period. 
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1.3 
Schedule of Activities 
The Schedule of Activities during the Screening and Treatment Periods is provided in Table 1-1. 
The Schedule of Activities during the Extension and SFU Periods are presented in Table 1-2. 
The PK sampling will be performed according to the schedule provided in Table 1-3. 
 
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Table 1-1: 
Schedule of Activities – Screening and Treatment Periods 
Assessments 
Screening Period a 
Treatment Period 
0h to 96h 
Up to 36h 
-36h to 
up to 
 -2h 
Baseline 
Period b 
 
up to -2h 
to 0h 
0h 
3h 
8h 
16h 
24h 
32h 
40h 
48h 
56h 
64h 
72h 
80h 
88h 
96h c 
Early 
Withdrawal 
Evaluation for 
efficacy d 
(Assessment window) 
- 
- 
- 
(±15min) 
(±60min) 
Informed consent e 
X 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographic data 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
including Apgar score 
and Sarnat scale f 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vital signs g 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physical and 
neurological 
examinations 
 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Length 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Body weight h 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
 
 
X 
X 
Head circumference 
X i 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Primary cause of 
seizure 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
X j 
X j 
ECG g 
X 
X g 
 
 
 
 
X g 
 
 
 
 
 
X g 
 
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Table 1-1: 
Schedule of Activities – Screening and Treatment Periods 
Assessments 
Screening Period a 
Treatment Period 
0h to 96h 
Up to 36h 
-36h to 
up to 
 -2h 
Baseline 
Period b 
 
up to -2h 
to 0h 
0h 
3h 
8h 
16h 
24h 
32h 
40h 
48h 
56h 
64h 
72h 
80h 
88h 
96h c 
Early 
Withdrawal 
Evaluation for 
efficacy d 
(Assessment window) 
- 
- 
- 
(±15min) 
(±60min) 
AED treatment  
(PB, LEV or MDZ, 
[additional BZDs 
allowed]) 
X k 
X 
 
 
X l 
Video-EEG m 
X 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LCM infusion  
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X n 
 
Active Comparator 
 
 
X o 
 
LCM PK samples p 
 
 
X 
 
Laboratory 
assessments (safety) q 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
AEs 
X 
Concomitant 
medications 
X 
Medical procedures 
X 
AEDs k 
X 
AE=adverse events; AED=antiepileptic drug; BZD=benzodiazepine; ECG=electrocardiogram; ENS=electroencephalographic neonatal seizures; h=hours; 
HIE=hypoxic-ischemic encephalopathy; ICF=Informed Consent form; IRT=Interactive Response Technology; iv=intravenous; LCM=lacosamide; 
LEV=levetiracetam; MDZ=midazolam; min=minutes; PB=phenobarbital; PK=pharmacokinetic; SFU=Safety Follow-up; StOC=standard of care; 
video-EEG=video-electroencephalogram 
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a Screening Period is from signing and dating of the written ICF up to initiation of the first dose of study medication. 
b The duration of the Baseline video-EEG depends on seizure activity. Study participants with intermittent seizures will enter the Treatment Period based on up 
to 2 hours of video-EEG recording. Study participants in status epilepticus will enter the Treatment Period based on up to 30min of video-EEG recording, ie, as 
soon as 15min of continuous seizures or 50% of cumulative seizure activity is confirmed on video-EEG. 
c If study participants do not benefit from LCM treatment after 96h of LCM administration, LCM administration will be stopped and the participant will be 
treated per the StOC. Study participants discontinuing LCM treatment during the Treatment Period will enter the SFU Period with optional down titration. 
d The evaluation for efficacy will start 1h after initiation of randomized treatment (LCM or Active Comparator) and will be used for evaluation of the primary 
endpoint based on video-EEG. 
e Parent(s) or legal representative(s) will be informed about the study as early as possible and asked to sign the ICF. 
f The Sarnat scale will be used to measure the severity of HIE for study participants with HIE. 
g For study participants in the LCM group only. Electrocardiograms to be taken during the Screening Period (-24h to 0h), postdose (1-6h), at 48h, and at 96h. 
The ECG postdose 1-6h preferred to be taken as close to the first hour as possible.  
h Measurement of body weight is optional at 24h, 48h, 72h, and 96h. Dosage of LCM during the Treatment Period will be based on the study participant’s weight 
measured prior to the start of the first LCM administration. However, dosage calculation can be adjusted to a more recent weight measurement, upon discretion 
of the investigator, if weight is measured during the Treatment Period. 
i Head circumference Baseline measurement should be taken within 7 days prior to drug administration, or at birth for study participants ≤7 days old. 
j In case of new information gained since the initial assessment. 
k The recording of AEDs will include BZDs and opiates taken by the mother at the time of delivery. 
l Optional for that day. 
m Video-EEG acquired per StOC prior to consenting and meet the study-specific technical and quality requirements can be used as part of the Baseline 
assessment video-EEG. 
n Lacosamide will be administered three times a day, as an iv infusion over 30min. The actual LCM dose during the study for each study participant will be 
provided by IRT. Treatment Period dosing will be up to the 96h timepoint; however, at 96h the study participant may enter the Extension period and receive 
LCM either as oral solution or iv infusion.  
o Standard of care, based on local practice and treatment guidelines. 
p For participants randomized to LCM treatment, blood microsamples (0.2mL/sample) will be collected following the first LCM infusion and during the 
Treatment Period. Samples collected at 48, 72 and 96 hours (Days 2, 3 and 4) are optional. Refer to Table 1-3 for further detail on PK sampling times. 
q For Screening and determination of eligibility, use of laboratory data acquired prior to Screening per StOC inside or outside the study site within 36h prior to 
the start of the Treatment Period is allowed. For the 24h and 96h assessments, the window is ±12h. 
 
 
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Table 1-2: 
Schedule of Activities - Extension and Safety Follow-up Periods 
Assessments 
Extension Period 
Safety Follow-up Period a 
(with optional down titration) 
Up to 28 days of PNA or 
withdrawal 
14 days 
(Down titration b for 7 days) 
q7d 
Day 14 
(Assessment window) 
(±2 days) 
(±2 days) 
Vital signs 
X 
X 
Physical and neurological examination 
X 
X 
Biometric parameters: length, body 
weight and head circumference 
 
X 
LCM c or Active Comparator 
administration or dispense d 
X 
Laboratory assessments (safety) e 
X 
X 
AEs 
X 
X 
ECG 
X 
X 
Concomitant medications 
X 
X 
Medical procedures 
X 
X 
AEDs 
X 
X 
AE=adverse event; AED=anti-epileptic drug; ECG=electrocardiogram; IRT=Interactive Response Technology; 
iv=intravenous; LCM=lacosamide; PNA=postnatal age; q7d=every 7 days; SFU=Safety Follow-up. 
a All study participants will enter the SFU Period after the Extension Period or if they withdraw from the study at 
any time. Study participants return to the site for the SFU visit at the end of the 14-day (± 2 days) SFU Period. 
b Down titration is recommended for study participants in the LCM treatment group who withdraw from the study. 
c The actual dose of LCM will be provided by IRT. 
d The study participants in the LCM treatment group must be switched to LCM oral solution as soon as medically 
possible, and be able to tolerate it. The timing of switching from iv to oral solution in the Extension Period will be 
at the discretion of the investigator. 
e Routine safety laboratory assessments performed within 2 days are acceptable. For participants who withdraw, 
safety laboratory assessments should be performed in a window of ±12 hours. 
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Table 1-3: 
Schedule for PK sampling 
Assessment 
96-hour Treatment Period 
 
Day 1 
Day 2 a 
Day 3 a 
Day 4 a 
30 to 90min 
after start of 
first infusion 
6 to 8h after 
start of first 
infusion 
30 to 90min 
after start of 
second or 
third 
infusion 
6 to 8h 
after start 
of second 
or third 
infusion 
 
 
 
LCM 
PK samples  
X 
X 
X 
X 
X 
X 
X 
h=hours; LCM=lacosamide; min=minutes; PK=pharmacokinetic 
Note: Blood for PK samples should be drawn from a limb different to that of the LCM infusion if using an existing 
line, or as a subsample of a safety laboratory assessment blood draw, or may be obtained by heel prick. Blood 
volume per PK sample will not exceed 0.2 mL (use Sarstedt MicrovetteTM 200 containers with conical inner tube, 
serum/activator type). 
a One optional sample per day, preferably obtained shortly before dosing (trough sample) or at any other postdose 
time point (but never during infusion). 
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2 
INTRODUCTION 
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 hypoxic-ischemic 
encephalopathy (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 
video-electroencephalogram (video-EEG) recordings, especially following anti-epileptic drug 
(AED) treatments, electroencephalographic neonatal seizures (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 phenobarbital (PB) and phenytoin (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 midazolam (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, levetiracetam (LEV), lidocaine (LDC), 
and MDZ (Slaughter et al, 2013). 
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 (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. 
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2.1 
Study Rationale 
Thus far, lacosamide (LCM) is approved for treatment of partial-onset seizures for patients 
≥1 month of age in the United States. SP0967 investigated safety, tolerability, and efficacy of 
LCM in children with epilepsy aged ≥1 month to <4 years of age. SP0967 has been completed 
with no safety issues identified by safety monitoring and an external Data Monitoring Committee 
(DMC). Lacosamide is available as tablets, oral solution, and intravenous (iv) formulation. A 
study of safety and tolerability of the iv formulation has recently been completed in children with 
epilepsy down to the age of 1 month (EP0060) with an infusion duration of 15 to 60 minutes. 
Lacosamide was well tolerated in that study and no safety issues were identified. 
Lacosamide for the treatment of seizures in the context of chronic epilepsy should be titrated up 
in weekly steps to reduce CNS and cardiovascular side effects. Acute seizures, such as acute 
neonatal seizures, require immediate treatment and rapid effective serum levels, which can only 
be achieved by a loading dose. Safety and tolerability of a loading dose in children has been 
completed in a retrospective real world evidence (RWE) study that included neonates, and also 
informed on dosing usage patterns (EP0147). 
SP0968 represents the first clinical study of LCM in neonatal study participants, and will 
evaluate the efficacy, safety, and pharmacokinetics (PK) of LCM in neonates (≥34 weeks of 
CGA, <46 weeks of CGA, and <28 days of PNA). 
2.2 
Background 
Lacosamide (VIMPAT®, SPM 927, previously referred to as harkoseride, (R)-2-acetamido-N-
benzyl-3-methoxypropionamide, or Anticonvulsant Drug Development [ADD] 234037 [used by 
the National Institutes of Health during the ADD Program]) is a member of a series of 
functionalized amino acids that were specifically synthesized as anticonvulsive drug candidates. 
Lacosamide belongs to a novel class of functionalized amino acids. It has minimal protein 
binding and effect on cytochrome P450 enzyme system function (reducing the risk of drug-drug 
interactions), high oral bioavailability (F), and a half-life of approximately 13 hours (in adults), 
which allows a twice daily (bid) dose regimen. It also displays dose-proportional PK following 
administration over a range of doses up to 800mg in adults. 
Lacosamide has been approved worldwide in over 70 countries. In the US, oral tablets, oral 
solution (syrup), and iv solution of LCM are indicated for the treatment of partial-onset seizures 
in patients ≥1 month of age.  
In the European Union, LCM oral tablets, oral solution (syrup), and solution for iv infusion are 
indicated as monotherapy and adjunctive therapy in the treatment of partial-onset seizures with 
or without secondary generalization in patients ≥4 years of age. The iv formulation at infusion 
durations of 15 to 60 minutes bid is indicated as an alternative for patients when oral 
administration is temporarily not feasible. 
The oral solution (also referred to as syrup) is a formulation suitable for administration to 
children. Bioequivalence has been shown between the tablet and oral solution formulations, 
comparing 2 tablets of LCM 100mg and the oral solution containing LCM 200mg, after 
single-dose administration in healthy study participants. The PK of LCM and SPM 12809 (major 
LCM metabolite in humans) in plasma, urine, and saliva were identical or very similar after 
single oral doses of LCM 200mg administered as tablets or as oral solution. 
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2.2.1 
LCM in pediatric studies 
In a systematic review of AEDs used in the treatment of partial-onset seizures, the AEDs that 
were shown to be superior to placebo for the adjunctive treatment of partial-onset seizures in 
adult clinical studies were also shown to be superior to placebo for adjunctive treatment of 
partial-onset seizures in the pediatric clinical studies (study participants >2 years of age) in 
which they were investigated (Bourgeois and Goodkin, 2012; Pellock et al, 2012). The efficacy 
and safety of LCM observed in clinical studies in adults and preclinical data, as well as many 
additional attributes of LCM, render the drug appropriate to investigate in pediatric study 
participants. These attributes include predictable and linear PK, lack of drug-drug interactions, 
easy bid dosing, and the availability of 3 different types of formulations in multiple strengths 
(allowing for flexibility in dose range and individualization of treatment). 
Lacosamide is being evaluated in pediatric study participants ≥1 month to 17 years of age with 
partial-onset seizures in completed and 1 ongoing study. The completed and ongoing pediatric 
studies are summarized in Table 2-1. Preliminary data have not demonstrated any clinically 
relevant changes in vital signs, electrocardiograms (ECGs), or clinical laboratory values; or 
evidence of cardiac-related treatment-related adverse events or body weight changes. 
Table 2-1: 
Overview of ongoing and completed studies of LCM in partial-
onset seizures that include study participants <17 years of age 
Study 
number 
Study description 
LCM dosage (route of 
administration) a 
Status 
SP847 
A Phase 2, multicenter, open-label study to 
investigate the safety, tolerability, and 
pharmacokinetics of LCM oral solution (oral 
solution) as adjunctive therapy in pediatric study 
participants (≥1 month to ≤17 years of age) with 
partial-onset seizures 
2 to 12mg/kg/day (oral 
solution) 
Complete 
SP1047 
A Phase 1, multicenter, open-label study to 
investigate the pharmacokinetics of commercial 
oral LCM in pediatric study participants 
(≥1 month to ≤17 years of age) with epilepsy 
15mg/mL (oral solution), 
50 to 200mg (tablet), or 
10mg/mL (oral solution) 
at the clinically 
prescribed dose 
Complete 
SP0969 
A Phase 3, multicenter, double-blind, 
randomized, placebo-controlled, parallel-group 
study to investigate the efficacy and safety of 
LCM as adjunctive therapy in pediatric study 
participants (≥4 years to <17 years of age) with 
partial-onset seizures 
6 to 12mg/kg/day (oral 
solution),  
300 to 400mg/day (tablet) 
Complete 
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Table 2-1: 
Overview of ongoing and completed studies of LCM in partial-
onset seizures that include study participants <17 years of age 
Study 
number 
Study description 
LCM dosage (route of 
administration) a 
Status 
EP0060 
A Phase 2/3 multicenter, open-label study to 
investigate the safety and tolerability of iv LCM 
in children (≥1 month to <17 years of age) with 
epilepsy 
If switching from oral to 
iv: 2 to 12mg/kg/day or 
100 to 600mg/day 
 
If initiating LCM 
treatment: 
For <50kg: 1mg/kg, bid 
For ≥50kg: 50mg, bid 
Complete 
SP848 
A Phase 2, multicenter, long-term, open-label 
study to determine safety, tolerability, and 
efficacy of oral LCM as adjunctive therapy in 
pediatric study participants (≥1 month to 
≤17 years of age) with epilepsy, previously 
enrolled in SP847, SP0966, or directly enrolled 
2 to 12mg/kg/day (oral 
solution),  
100 to 600mg/day (tablet) 
Complete 
SP0967 
A Phase 3, multicenter, double-blind, 
randomized, placebo-controlled, parallel-group 
study to investigate the efficacy and safety of 
LCM as adjunctive therapy in pediatric study 
participants (≥1 month to <4 years of age) with 
partial-onset seizures 
8 to 12mg/kg/day (oral 
solution) 
Complete 
EP0034 
A Phase 3, multicenter, open-label, extension 
study to obtain long-term safety and efficacy of 
LCM oral solution or LCM tablets as adjunctive 
therapy in pediatric study participants (≥1 month 
to ≤17 years of age) with partial-onset seizures 
previously enrolled in SP0967 or SP0969 
Up to 12mg/kg/day or 
600mg/day 
Ongoing 
bid=twice daily; iv=intravenous; LCM=lacosamide 
a Daily dose, unless otherwise specified. 
2.3 
Benefit/Risk Assessment 
Due to growing evidence that neonatal seizures contribute to an adverse neurodevelopmental 
outcome, physicians are increasingly focused on the diagnosis and treatment of neonatal seizures 
(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 (Ramantani et al, 2019; van Rooij et al, 
2013a), and no AED is approved for the treatment of neonatal seizures. First-generation AEDs, 
such as PB, PHT, and LDC, remain the drugs of first (and second) choice because of extensive 
clinical experience, despite their limited clinical effectiveness, unpredictable PK, and potential 
neurotoxicity (van Rooij et al, 2013b). Therefore, studies to assess the PK, efficacy or 
effectiveness, and safety of new treatment options in neonates are warranted. 
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Lacosamide has shown efficacy and is approved for use in children ≥1 month of age in the 
United States. A clinical study in participants with partial-onset seizures from ≥1 month to 
<4 years of age (SP0967) has been completed and a study of safety and tolerability of LCM iv 
formulation has recently been completed in children with epilepsy down to the age of 1 month 
(EP0060); no safety signal has emerged from either study. Moreover, other sodium channel 
blocking AEDs (such as PHT and LDC) have shown efficacy in the treatment of neonatal 
seizures (Painter et al, 1999; Boylan et al, 2004) and are included as StOC treatment. 
Lacosamide, as a sodium channel blocking AED, may be expected to have efficacy. Based on the 
efficacy in older pediatric population and on the assumed efficacy of other sodium channel 
blockers in neonatal seizures, LCM will potentially be effective in reducing seizure burden in 
neonates with seizures that are not adequately controlled with first-line or later-line treatment. 
The dosing in SP0968 is based on modeling with data from children ≥1 months of age. 
Pharmacokinetic analysis is planned on an ongoing basis as study participants are enrolled in 
SP0968. 
There is extensive safety information for LCM across different pediatric age groups and seizure 
types from different sources. As of Aug 2021, 5778 study participants received LCM while 
participating in UCB clinical studies for epilepsy including 969 pediatric participants. A clinical 
study in partial-onset seizures in participants ≥1 month to <4 years of age (SP0967) has been 
completed. The clinical development program included 141 participants <2 years of age and no 
safety signal has emerged in that study population. In the UCB Global Safety Database, during 
the period from 01 Sep 2018 to 31 Aug 2021, 28 initial (4 serious and 24 nonserious) 
postmarketing cases were reported for participants aged 0 to 1 month. Of the 4 serious cases, 
3 cases reported seizure/epilepsy along with drug ineffective/multiple-drug resistance; all 
involved use of multiple ASMs. Limited information was reported in the remaining 1 serious 
case with hospitalization. Of the 24 nonserious cases, 23 cases reported no associated clinical 
events and 1 case reported vomiting that recovered after discontinuation of LCM. An RWE study 
was completed and provided further information on usage patterns and the safety of loading dose 
of LCM in children, including neonates (EP0147).  
The most relevant known adverse drug reactions (ADRs) of LCM, across all age groups for 
which LCM is approved, which are expected to be relevant for the neonatal population, are 
cardiac ADRs (potentially associated with PR interval prolongation or sodium channel 
modulation), potential for hepatotoxicity, and potential for worsening of seizures. The effect of 
LCM treatment on the development of a neonate is unknown, but long-term safety information 
from studies in older children as well as long-term data from pregnancy registries show no 
evidence of adverse effects on long-term outcome and development. 
While the exposure in neonates is still limited, the safety profile of LCM in all other pediatric 
age groups is acceptable, which is reassuring for the neonate population. 
In order to ensure safety during the study conduct of SP0968, continuous safety monitoring will 
be conducted internally and at intervals through the DMC (Section 9.8). All participants will be 
under constant surveillance in Neonatal Intensive Care Unit (NICU) with video-EEG monitoring 
and cardiovascular monitoring as appropriate. Long-term safety will be assessed for participants 
progressing to long-term safety follow up, when applicable. A safety reporting process is 
planned to ensure that the UCB study physician and safety physician are informed in real time 
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about serious adverse events (SAEs) or other AEs deemed important by the investigator for the 
evaluation of safety. 
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of LCM may be found in the Investigator’s Brochure (IB). The current IB reflects 
the safety profile of LCM as it is known and may change with the accumulation of additional 
data. 
3 
OBJECTIVES AND ENDPOINTS 
Objectives 
Endpoints 
Primary 
• 
To evaluate the efficacy of LCM vs an 
Active Comparator chosen based on StOC 
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 
• 
Reduction in seizure burden measured in the 
Evaluation a video-EEG compared with the 
Baseline video-EEG 
Secondary 
• 
To further evaluate the efficacy of LCM vs 
an Active Comparator 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 
• 
Proportion of responders in the Evaluation a 
video-EEG compared with the Baseline 
video-EEG 
• 
Proportion of participants with at least 80% 
reduction in seizure burden in the Evaluation a 
video-EEG compared with the Baseline 
video-EEG 
• 
Time to response across the first 48-hours of the 
Treatment Period compared with the Baseline 
video-EEG 
• 
Time to seizure freedom across the first 48-
hours of the Treatment Period compared with 
the Baseline video-EEG 
• 
Absolute reduction in seizure burden across the 
first 48-hours of the Treatment Period measured 
by continuous video-EEG compared with the 
Baseline video-EEG 
• 
Percent reduction in seizure burden across the 
first 48-hours of the Treatment Period measured 
by continuous video-EEG compared with the 
Baseline video-EEG 
• 
Proportion of responders at the end of the first 
48-hours of the Treatment Period 
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Objectives 
Endpoints 
• 
Proportion of study participants who are 
seizure-free (100% reduction in seizure burden 
from Baseline) at 24 hours after the start of the 
Treatment Period, categorized by study 
participants with nonsevere or severe seizure 
burden at Baseline 
• 
Categorized percentage reduction in seizure 
burden in the Evaluation a video-EEG compared 
with the Baseline video-EEG (<-25% 
[worsening], -25% to <25% [no change], 
25% to <50%, 50% to <80%, and ≥80%) 
• 
To evaluate the short-term safety and 
tolerability of LCM in neonates 
• 
TEAEs as reported by the investigator 
• 
Percentage of treatment-emergent marked 
abnormalities b in 12-lead ECG 
• 
To evaluate the PK of LCM in neonates 
who have seizures that are not adequately 
controlled with previous AED treatment 
• 
Mean serum concentration of LCM 
Other 
• 
To further evaluate the short-term safety 
and tolerability of LCM in neonates 
• 
Percentage of treatment-emergent marked 
abnormalities b in hematology and chemistry 
parameters 
• 
Percentage of treatment-emergent marked 
abnormalities b in vital sign measurements 
(ie, BP and pulse rate) 
• 
Change from Baseline in physical and 
neurological examination at 24 hours, 48 hours, 
72 hours, and 96 hours after the start of initial 
treatment 
AE=adverse event; AED=anti-epileptic drug; BP=blood pressure; ECG=electrocardiogram; 
ENS=electroencephalographic neonatal seizures; LCM=lacosamide; PK=pharmacokinetics; StOC=standard of 
care; TEAE=treatment-emergent adverse event; video-EEG=video- electroencephalogram 
a The 2-hour evaluation for efficacy will start 1 hour after initiation of randomized treatment (LCM or Active 
Comparator) and will be used for evaluation of the primary endpoint based on video-EEG. 
b Marked abnormalities will be defined in the Statistical Analysis Plan 
4 
STUDY DESIGN 
4.1 
Overall design 
SP0968 is a Phase 2/3, multicenter, open-label, randomized, active comparator study to evaluate 
the efficacy, safety, and PK of LCM in neonates with repeated ENS compared with an Active 
Comparator chosen based on StOC per the local practice and treatment guidelines. Only those 
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study participants who do not have adequate seizure control with previous AED treatment will be 
permitted to enroll in SP0968. 
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). Study participants 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. Parent(s) or legal representative(s) 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. 
4.1.1 
Video-EEG 
Video-EEG will be used for the assessment of the study entry criteria and for the assessment of 
the efficacy endpoints. 
Video-EEG recording needs to have started at least 2 hours before treatment randomization and 
will continue for 48 hours after administration of the first dose of randomized treatment. The 
video-EEG recording can be shortened per clinical need (eg, if status epilepticus is detected). If 
justifiable, an attempt should be made to record at least 30 minutes of Baseline video-EEG. 
Interruption of the video-EEG is allowed up to 3 hours per day. There should be no interruptions 
in the video-EEG for the first 3 hours. Depending on medical needs (eg, magnetic resonance 
imaging to be performed), interruptions longer than this are acceptable. Interpretation of 
video-EEGs will be done by local readers for care decisions. Start and stop of randomized 
treatment (LCM or Active Comparator), and the administration of rescue medication will be 
digitally marked as treatment events on video-EEGs. 
The video-EEGs will subsequently be evaluated by a blinded, independent central reader. The 
independent central reader will be blinded from site-specific information and the study 
participant’s medical history. The video-EEG data should be saved, stored, anonymized, and 
delivered to the independent central reader in an expeditious manner. 
4.1.2 
Study periods 
The study will consist of the following periods (Figure 1-1): 
Screening Period (-36 hour to 0 hour) 
The Screening Period will start from the signing and dating of the written ICF and is up to 
36 hours prior to the initiation of the first randomized dose of study treatment. During this 
period, study participants must have been administered StOC treatment (based on local 
practice and treatment guidelines). These treatments for ENS include LEV, PB, or MDZ (in 
any combination). Other BDZ may have been given additionally. Sodium channel blockers 
(such as PHT or LDC) are not permitted prior to enrollment but are allowed as options for 
the Active Comparator. The previous AED treatments may have been administered at a 
location other than the study site. 
− Baseline (-2 hours to 0 hour) 
Baseline is defined as the final 2 hours of the Screening Period. During these 2 hours, 
study participants will continue to receive the routine care of the NICU and the AED 
treatment must not be changed. Baseline assessments need to be conducted before 
randomization including seizure burden assessments (refer to Section 8.1.1.1.1 for details 
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on seizure burden [severe vs nonsevere] assessment). The interpretation of the Baseline 
video-EEG should be done immediately before randomization. 
Treatment Period (0 hour to 96 hour) 
Following the Baseline assessments, study participants will be randomized 1:1 to either LCM 
or the Active Comparator (based on StOC). The randomization will be stratified by seizure 
severity. 
− Evaluation (end of 1st hour to the 3rd hour) 
The 2-hour Evaluation will start 1 hour after initiation of randomized treatment (LCM or 
Active Comparator) and will be used for evaluation of the primary endpoint based on 
video-EEG. 
The Treatment Period will continue through 96 hours or until the decision to stop treatment is 
made. Rescue medication, if needed, can be administered during the Treatment Period. 
Ideally, rescue medication will not be given within the first 3 hours of randomized treatment; 
however, the administration of rescue medication will always be at the discretion of the 
investigator. For details on rescue medication refer to Section 6.5.3. 
For study participants randomized to LCM treatment, LCM will be administered as an 
iv infusion over 30 minutes. A dose of LCM 15mg/kg/day is estimated to yield 
approximately the same plasma concentrations as in an adult receiving LCM 400mg/day. The 
planned LCM dose in the study may be adjusted during the study as more PK information in 
neonates is obtained from ongoing studies and as SP0968 progresses; thus, participants in 
this study are planned to be treated at the most appropriate dose, based on evolving 
cumulative knowledge. The actual LCM dose during the study for each study participant will 
be provided by Interactive Response Technology (IRT). 
The recommendation to adjust the LCM dose will be given by the DMC after review of 
cumulative PK and safety data. The sponsor will review the data periodically and inform the 
investigators if dose modification is needed. For details of the safety data review and data 
monitoring, refer to Section 9.8. 
Following the first LCM administration, blood microsamples (0.2mL sample) will be 
collected during the 96-hour Treatment Period for each study participant for the 
determination of serum concentrations of LCM, at time points described in Table 1-3. Blood 
for PK samples should be drawn from a limb different to that of the LCM infusion if using an 
existing line, or as a subsample of a safety laboratory assessment blood draw, or may be 
obtained by heel prick. 
For study participants randomized to Active Comparator, the Active Comparator treatment 
will be chosen and dosed based on StOC (per local practice and treatment guidelines). 
At the end of the Treatment Period, study participants may continue to receive randomized 
treatment in the Extension Period. Study participants who discontinue treatment during the 
Treatment Period will enter the Safety Follow-up (SFU) Period. If study participants do not 
benefit from LCM treatment after 96 hours of LCM administration, LCM administration will 
be stopped and the participant will be treated as per StOC. 
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Study assessments will be performed at the time points outlined in the Schedule of Activities 
for the Screening and Treatment Periods in Table 1-1. Blood sampling for PK during the 
Treatment Period will be performed at time points outlined in Table 1-3. 
Extension Period (up to 28 days of PNA) 
During the Extension Period study participants who remain inpatient have the option to 
continue to receive the treatment (LCM or Active Comparator) based on their treatment 
group. 
During the Extension Period, study participants in the LCM treatment group may continue 
receiving the same LCM dose administered at the end of the Treatment Period; the LCM 
dose should not be increased, but may be decreased, at the discretion of the investigator. 
Participants should be switched to oral dosing of LCM as soon as medically possible during 
the Extension Period. Oral dosing of LCM can be three times a day (tid) or bid. 
During the Extension Period, study participants in the Active Comparator group will 
continue to receive the Active Comparator with dosing and route of administration chosen 
based on the StOC. 
Study assessments during the Extension Period will be performed every 7 days, starting from 
the end of the Treatment Period. Study participants will be hospitalized during this period. 
The Extension Period covers days and treatments while hospitalized until 28 days of PNA or 
until the participant is discharged from hospital, whichever occurs first. 
At the end of the Extension Period or if discontinuing from the Extension Period, study 
participants will enter the SFU Period. 
Study assessments will be performed at the time points outlined in the Schedule of Activities 
for the Extension and SFU Periods in Table 1-2. 
Safety Follow-up Period (with optional down titration) (14 days) 
Study participants who discontinue the randomized study treatment at any time, complete the 
Extension Period, are discharged from the hospital, or reach 28 days of PNA, will enter the 
14-day SFU Period. 
For study participants in the LCM treatment group, the SFU Period includes an option to 
down titrate their LCM dose over 7 days. Down titration is recommended for study 
participants who discontinue LCM treatment. It is recommended that the LCM dose be 
tapered in daily decrements of 3mg/kg/day. 
Study participants will return to the site for the SFU visit at the end of the 14-day SFU 
period. 
4.2 
Scientific rationale for study design 
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. 
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The current accepted medical practice for neonatal seizures is initial treatment with PB with 
rapid progression to treatment with MDZ, LEV, LDC, or PHT for patients without adequate 
seizure control after 2 doses of PB. Some clinics start treatment with LEV based largely on its 
favorable safety profile. In up to 50% of patients, 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, SP0968 is designed for a flexible treatment of ENS, and 
only those participants who do not have adequate seizure control with previous AED treatment 
will be permitted to enroll in the study. 
The frequency, voltage, and morphology of the discharges may change within an individual 
seizure and between seizures in an individual neonate. At enrollment, study participants must be 
≥34 weeks of gestationally-corrected age (GCA), <46 weeks of CGA, and <28 days of PNA. 
Neonates undergoing hypothermia treatment (eg, for the treatment of HIE) will also be enrolled. 
4.3 
Justification for dose 
A pediatric population PK model of LCM (CL0447 Part-IV) was developed using demographic 
information, dosing records, and LCM plasma concentration measurements, obtained across 
6 Phase 2 and Phase 3 studies in children with epilepsy (SP847, SP1047, SP848, SP0969, 
SP0966, SP0982 pediatric cohort, EP0060, and SP0967). Lacosamide was generally 
administered orally, except in EP0060 in which participants were dosed iv. Overall, 705 children 
aged from ≥1 month to <17 years of age, contributed PK information; among them, 95 had been 
dosed iv in EP0060. The 2 youngest pediatric cohorts, from ≥1 month to <1 year and from 
≥1 year to <2 years, numbered 44 and 48 participants, respectively. 
A 1-compartment PK model with fixed allometric exponent for distribution volume (Vc) and 
freely estimated allometric exponent for clearance (CL), and with F implemented on the logit 
scale, fitted the data well. Incorporating a sigmoid-Emax maturation function to the expression of 
CL resulted in significant improvement. The typical parameter values were: 1.74L/h for CL and 
45.4L for Vc (both normalized to 70kg), 0.847 for F, 0.467 for CL allometric exponent, and 
1.50 h-1 for absorption rate constant (Ka), respectively. 
The optimal LCM dosing regimen in newborns is aimed at achieving plasma concentrations in 
the range of adults dosed at LCM 400mg/day. The reference concentration range was obtained 
from the main population PK model (CL0447 Part-IV) and was derived from observed PK in 
950 adult study participants across Phase 3 studies (SP754, SP755, EP0008, and SP0982). 
For extrapolation of the model to newborns, weight and age data were randomly sampled from 
the National Health and Nutrition Examination Survey database. Simulated dosing in newborns 
included 5 days of iv dosing followed by oral dosing. Lacosamide plasma half-life was predicted 
to be significantly shorter in newborns (mean: 7.97 hours; 90% confidence interval [CI]: 7.69 to 
8.25 hours) compared with adults (approximately 15 to 16 hours). 
The optimal dosing regimen was found to involve initial iv dosing at 5mg/kg tid (or every 
8 hours [q8h]) during 5 days, followed by oral dosing at 5mg/kg tid or at 7.5mg/kg bid (or every 
12 hours [q12h]) for newborns and infants weighing <6kg. In contrast, optimal dosing for 
children weighing ≥6kg to <30kg was estimated to be 6mg/kg bid both iv and orally. Of note, 
given the predicted rapid CL or short half-life of LCM in newborns, simulations indicated that a 
loading dose was not justified in this population.  
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The planned LCM dosing in SP0968 is based on the simulations described above and will not 
involve any dose titration. Since extrapolation from infants to newborns is based on limited 
amounts of data and may be imprecise due to variability in ontogeny in the metabolic and 
excretory functions, actual PK measurements conducted in SP0968 will be used to confirm the 
relationship between LCM dose and serum concentration in neonates. 
Furthermore, the posology of LCM is proposed as an approximately 30-minute iv infusion and is 
supported by PK and safety data available from study participants ≥1 month old (EP0060). 
4.4 
End of study definition 
The end of the study is defined as the date of the last visit of the last participant in the study. 
5 
STUDY POPULATION 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1 
Inclusion criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
Age 
1a. Participant must be ≥34 weeks of CGA, <46 weeks of CGA, and <28 days of PNA, at the 
time of signing the informed consent. 
Type of participant and disease characteristics 
2a. Participants who have confirmation on video-EEG of ≥2 minutes of cumulative ENS or 
≥3 identifiable ENS prior to entering the Treatment Period (ENS is defined as a seizure 
lasting for at least 10 seconds on video-EEG), despite receiving previous AED treatment for 
the treatment of electroencephalographic seizures. 
The occurrence of ENS during an up to 2-hour period, with at least 30 seconds of cumulative 
ENS in an hour, must be confirmed by the local video-EEG reader prior to randomized study 
drug administration. Video-EEG recording can be shortened per clinical need (eg, if status 
epilepticus is detected). If possible, an attempt should be made to record at least 30 minutes 
of Baseline video-EEG. 
3.  Participants must have received either PB, LEV, or MDZ (in any combination) before 
entering the study. 
4.  Participants with or without concomitant hypothermia treatment. 
Weight 
5.  Participant weighs at least 2.3kg at the time of enrollment. 
Informed consent 
6.  An Independent Ethics Committee (IEC)-approved written ICF is signed and dated by the 
participant’s parent(s) or legal representative(s). 
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5.2 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
Medical conditions 
1. Participant with seizures responding to correction of metabolic disturbances (hypoglycemia, 
hypomagnesemia, or hypocalcemia) or with seizures for which a targeted, known treatment is 
available. 
2. Participant has seizures related to prenatal maternal drug use or drug withdrawal. 
3. Participant has known severe disturbance of hemostasis, as assessed by the investigator. 
4. Participant has a poor prognosis for survival, as judged by the investigator. 
5. Participant has a medical condition that could be expected, in the opinion of the investigator, 
to interfere with study medication absorption, distribution, metabolism, or excretion. 
6. Participant has a clinically relevant ECG abnormality, in the opinion of the investigator 
(eg, second or third degree heart block at rest or a corrected QT interval [QTc] ≥450ms). 
7. Participant has a hemodynamically significant congenital heart disease. 
8. Participant has any clinically relevant cardiac arrhythmia. 
9a. If participant is in the first 24 hours of life, urine output is <1mL/kg/hour. If older than 
24 hours, participant urine output is <1mL/kg/hour or serum creatinine >1.7mg/dL.  
Prior/Concomitant therapy 
10. Participant receiving treatment with PHT, LDC, or other sodium channel blockers at any 
time. 
11. Participant requires extracorporeal membrane oxygenation. 
12. Participant requires or is expected to require phototherapy or exchange transfusion due to 
elevated bilirubin. 
Diagnostic assessments 
13. Participant 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 participants with perinatal asphyxia, elevation of AST, ALT, or ALP <5x ULN is 
acceptable, if initial and peak elevation of liver function tests (LFTs) occur 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 participant's CGA and the site’s normal 
range values for the respective CGA. 
14. Participant has direct (conjugated) bilirubin levels >2mg/dL. 
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5.3 
Lifestyle restrictions 
Not applicable. 
5.4 
Screen failures 
Screen failures are defined as participants who consent to participate in the clinical study, but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAE. 
If appropriate (in the event of screening failures), rescreening will be allowed for the study. 
Rescreening for screen-failed study participants will be allowed with prior consultation of the 
medical monitor, whenever feasible. Once a participant has received at least 1 dose of the study 
medication or has left the study because a “must withdrawal” criterion is met, rescreening will no 
longer be possible. 
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6 
STUDY TREATMENTS 
Study treatment is defined as any investigational treatment(s) or marketed product(s) intended to 
be administered to a study participant according to the study protocol. 
6.1 
Treatments administered 
A summary of the treatment administered is provided in Table 6-1. 
Table 6-1: 
Treatments administered 
Intervention name 
LCM 
Active Comparator 
Dose formulation 
iv for infusion a 
Oral solution b 
Based on local practice and 
treatment guidelines 
Unit dose strength(s) 
10mg/mL 
Dosage level(s) c 
X d mg/kg, tid, 
infusion over 
30 minutes 
Y d mg/kg, bid,  
oral 
Route of 
administration 
iv 
oral 
Use 
Test 
Reference 
IMP and NIMP 
IMP  
NIMP 
Sourcing 
Provided centrally by UCB  
Provided by investigational 
site 
Packaging and labeling 
Packaged in glass 
vials 
Packaged in amber 
bottles 
Per manufacturer’s label 
Clinical drug supplies will be labeled in 
accordance with the current ICH guidelines 
on GCP and GMP and will include any 
locally required statements. If necessary, 
labels will be translated into the local 
language. 
bid=twice daily; GCP=Good Clinical Practice; GMP=Good Manufacturing Practice; ICH=International Council for 
Harmonisation; IMP=investigational medicinal product; IRT=Interactive Response Technology; iv=intravenous; 
LCM=lacosamide; NIMP=noninvestigational medicinal product; tid=three times a day 
a Administered during Treatment Period. 
b Administered during Extension Period. 
c For LCM dose, the rounding rules for weight to dose calculations will be provided by IRT. 
d The actual dose of LCM will be provided by IRT. 
6.2 
Preparation, handling, storage, and accountability requirements 
The investigator (or designee) is responsible for the safe and proper storage of the investigational 
medicinal product (IMP) at the site. Investigational medicinal product stored by the investigator 
is to be kept in a secured area with limited access according to the storage conditions mentioned 
on the label. 
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Appropriate storage conditions must be ensured either by controlling the temperature or by 
completion of a temperature log in accordance with local requirements on a regular basis, 
showing minimum and maximum temperatures reached over the time interval. 
In case an out-of-range temperature is noted, it must be immediately reported as per instructions 
contained in the IMP Handling Manual. 
The investigator (or designee) will instruct the participant’s parent(s) or legal representative(s) 
(in accordance with local regulation) to store the IMP following the instructions on the label 
6.2.1 
Drug accountability 
A Drug Accountability form will be used to record IMP dispensing and return information on a 
by-participant basis and will serve as source documentation during the course of the study. 
Details of any IMP lost, damaged (due to breakage or wastage), not used, partially used, 
disposed of at the study site, or returned to the sponsor or designee must also be recorded on the 
appropriate forms. All supplies and pharmacy documentation must be made available throughout 
the study for UCB (or designee) to review. 
The IMP can either be returned or destroyed per the site’s drug destruction protocol/practice. 
The investigator may assign some of the investigator’s duties for drug accountability at the study 
site to an appropriate pharmacist/designee. 
The investigator must ensure that the IMP is used only in accordance with the protocol. 
Periodically, and/or after completion of the clinical phase of the study, all used (including empty 
containers/partially used), unused, damaged, and/or expired IMP must be reconciled and either 
destroyed at the site according to local laws, regulations, and UCB Standard Operating 
Procedures or returned to UCB’s designee. Investigational medicinal product intended for the 
study cannot be used for any other purpose than that described in this protocol. 
6.3 
Measures to minimize bias: Randomization 
To reduce the risk of imbalance between treatment groups with respect to seizure burden, 
randomization will be stratified based on seizure severity. A 1:1 (LCM:Active Comparator) 
randomization scheme will be used for the treatment allocation to participants in the study. 
Randomization will occur after completion of the End-of-Baseline video-EEG and after 
confirmation that the participant has met eligibility criteria.  
6.3.1 
Procedures for maintaining and breaking the treatment blind 
Not applicable; this is an open-label study. 
6.4 
Treatment compliance 
Site personnel who are administering LCM will record information about all doses administered, 
including the target dose, actual dose administered, and the dates and times of each 
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. 
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6.5 
Concomitant medication(s)/treatment(s) 
6.5.1 
Permitted concomitant treatments (medications and therapies) 
Concomitant treatment with non-AEDs is permitted at any time throughout the study. 
Concomitant treatment with AEDs during the Treatment Period after initiation of randomized 
treatment is permitted to continue in parallel with the LCM/Active Comparator treatment if study 
participants are on a stable dose from 1 hour prior to initiation of the LCM/Active Comparator 
treatment. Changes to concomitant AEDs are permitted from 3 hours onward following first 
LCM/Active Comparator administration. 
Sodium channel blockers are allowed for participants randomized to the Active Comparator 
treatment group. 
For study participants undergoing therapeutic hypothermia treatment, the target low body 
temperature achieved and age since birth when cooling began will be recorded. Rewarming of 
study participants will be documented in the same way. 
6.5.2 
Prohibited concomitant treatments (medications and therapies) 
Use of anti-arrhythmia medications is prohibited during LCM administration. 
Sodium channel blockers are prohibited for participants randomized to the LCM treatment 
group. 
6.5.3 
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 Treatment Period is considered rescue 
treatment. Rescue medication can be given at any time if considered necessary by the 
investigator. 
However, during the Treatment Period rescue medication should not be administered, if possible, 
in the following time frames: 
• During the first 3 hours after the initial dose of LCM/Active Comparator. If this occurs, 
participants will be considered nonresponders for the evaluation of the main efficacy 
variable. 
Rescue medication should be given if the following occurs: 
• There is no improvement in seizure burden within the first 3 hours after administration of 
LCM/Active Comparator. 
• 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 
LCM/Active Comparator. 
6.6 
Dose modification 
For participants in the Active Comparator treatment group, local treatment guidance will be 
followed if any dose modification is necessary. 
For participants in the LCM treatment group, the dose of LCM can be reduced based on clinical 
judgement of the investigator after the first dose. 
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6.7 
Criteria for study hold or dosing stoppage 
Serious adverse events and AEs of special interest will be monitored and triaged by the study 
physician and UCB Patient Safety (PS) in real time. After 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. 
UCB will take appropriate action based on DMC recommendation. 
Detailed procedures for reporting SAEs and other safety events which may meet study hold 
criteria are provided in Appendix 7 (Section 10.8). 
6.8 
Treatment after the end of the study 
Study participants who remain inpatient and who benefit from the LCM treatment may continue 
LCM if able to switch to oral LCM in the Extension Period. Continuation of LCM after the study 
is at the discretion of the treating physician based on the best interest of the participant. 
Lacosamide may be obtained by an expanded access program, if permitted by the local 
regulatory authority, or as commercial product if available/approved. 
7 
DISCONTINUATION OF STUDY MEDICATION AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1 
Discontinuation of study medication 
7.1.1 
Liver stopping criteria - potential drug-induced liver injury 
Study participants with potential drug-induced liver injury (PDILI) must be assessed to 
determine if IMP must be discontinued. In addition, all concomitant medications and herbal 
supplements that are not medically necessary should also be discontinued. 
The PDILI criteria below require immediate and permanent discontinuation of IMP: 
1. Study participant has direct (conjugated) bilirubin levels >2mg/dL. 
2. Study participant has AST, ALT, or ALP values 3x ULN, with the following exception: 
For participants 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 occur 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.  
The determination of ULN will be based on the study participant's CGA and the site’s normal 
range values for the respective CGA. 
3. Study participant requires or is expected to require phototherapy or exchange transfusion due 
to elevation of total bilirubin values. 
Specific assessments and follow-up actions for PDILI are provided in Appendix 6 (Section 10.6). 
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7.1.2 
ECG stopping criteria 
Electrocardiograms will be reviewed locally by the investigator or a qualified designee. If the 
reading identifies second or third degree atrioventricular (AV) block, a QTc ≥500ms, or another 
abnormal ECG finding that is assessed by the investigator to be clinically significant, then the 
study participant must be withdrawn from the study. 
Any new clinically relevant finding should be reported as an AE. 
7.1.3 
Temporary discontinuation 
Temporary discontinuation of LCM is not allowed in this study. 
7.1.4 
Rechallenge 
Rechallenge with LCM is not allowed in this study. 
7.2 
Participant discontinuation/withdrawal from the study 
Parent(s) or legal representative(s) are free to withdraw the participants from the study at any 
time, without prejudice to their continued care. 
Study participants must be withdrawn from the study if any of the following occur: 
1. The sponsor or a regulatory agency requests withdrawal of the study participant. 
2. Parent(s) or legal representative(s) withdraw their consent for the study participant to 
participate. 
3. Study participant requires phototherapy or exchange transfusion due to elevation of total 
bilirubin. 
4. Study participant has QTc interval of ≥500ms that is confirmed by a cardiologist over-read 
on any ECG. 
5. Study participant develops a second or third degree AV block. 
Study participants may be withdrawn from the study if any of the following events occur: 
1. Study participant experiences prolongation of seizure duration, a worsening of seizure 
burden, or emergence of a new seizure type considered by the investigator to require 
intervention. 
2. Investigator may withdraw study participant due to any medical condition, based on clinical 
judgment and discretion. 
3. Study participant requires a medication that is not permitted by the protocol. 
4. Study participant has AST, ALT, or ALP values between >2x and ≤3x ULN, with the 
following exception: 
For study participants with perinatal asphyxia, elevation of AST, ALT, or ALP <5x ULN is 
acceptable for continuation in the study, if initial and peak LFT elevation occur 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). 
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The determinations of ULN will be based on the study participant’s CGA and the site’s 
normal range values for the respective CGA. 
5. Study participant has rapidly increasing total bilirubin without requiring or being expected to 
require phototherapy or exchange transfusion; the participant’s withdrawal will be at the 
discretion of the investigator. 
Investigators should attempt to obtain information on participants 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 participant, must be recorded in the source documents. The electronic Case Report form 
(eCRF) must document the primary reason for withdrawal. 
Investigators should contact the Medical Monitor, whenever possible, to discuss the withdrawal 
of a participant in advance. 
7.3 
Lost to follow up 
During the Extension Period, a participant will be considered lost to follow up if he or she 
repeatedly fails to return for scheduled visits and the participant’s parent(s) or legal 
representative(s) is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant’s parent(s) or legal representative(s) and 
reschedule the missed visit as soon as possible and counsel the participant’s parent(s) or legal 
representative(s) on the importance of maintaining the assigned visit schedule and ascertain 
whether or not the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant’s parent(s) or legal representative(s) 
(at least 1 phone call and 1 written message to the participant’s parent[s] or legal 
representative[s]), and 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 participant, must be recorded in the source documents. The eCRF must 
document the primary reason for withdrawal. 
Should the participant’s parent(s) or legal representative(s) continue to be unreachable, the 
participant will be considered to have withdrawn from the study with a primary reason of lost to 
follow up documented in the eCRF. 
8 
STUDY ASSESSMENTS AND PROCEDURES 
Study procedures and their timing are summarized in the Schedules of Activities (Table 1-1 and 
Table 1-2). 
Protocol waivers or exemptions are not allowed. 
Immediate safety concerns should be discussed with the sponsor immediately upon occurrence or 
awareness to determine if the participant should continue or discontinue study treatment. 
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Adherence to the study design requirements, including those specified in the Schedule of 
Activities, is essential and required for study conduct. 
All screening evaluations must be completed and reviewed to confirm that potential participants 
meet all eligibility criteria. The investigator will maintain a screening log to record details of all 
participants screened and to confirm eligibility or record reasons for screening failure, as 
applicable. 
8.1 
Efficacy assessments 
Planned time points for all efficacy assessments are provided in the Schedules of Activities 
(Table 1-1 and Table 1-2). 
8.1.1 
Assessments of primary efficacy endpoints 
8.1.1.1 
Assessment of seizure burden 
For this study, an ENS is defined as an EEG seizure lasting for at least 10 seconds on 
video-EEG. Baseline seizure burden is defined as seizure burden measured on the continuous 
video-EEG (total ENS in minutes per hour) during a period of up to 2 hours immediately prior to 
the first administration of study drug. 
8.1.1.1.1 
Categorization of seizure burden severity by the investigator 
Categorization of seizure burden into severe vs nonsevere seizure burden will be used both for 
stratification across the 2 treatment groups as well as for responder criteria. 
For the categorization into severe vs nonsevere seizure burden, the investigator will evaluate the 
Baseline video-EEG. A participant is categorized as having severe seizure burden if there is any 
30-minute period of more than 50% seizure burden in the Baseline video-EEG, and as having 
nonsevere seizure burden otherwise. 
8.1.1.2 
Assessment of responder 
Seizure burden assessment will be based on the interpretations of the central reader. 
A responder is defined as a study participant who achieved the following reduction in seizure 
burden (Section 8.1.1.1) without need for rescue medication, compared with the seizure burden 
measured during the Baseline Period immediately prior to IMP administration, evaluated for a 
2-hour period starting 1 hour after the start of initial treatment: 
− At least 80% reduction of seizure burden in participants who were categorized as having 
nonsevere seizure burden during Baseline 
OR 
− At least 50% reduction of seizure burden in participants who had at least one 30-minute 
period of severe seizure burden during Baseline 
For the analysis of the efficacy endpoints, study participants will be considered nonresponders if 
any of the conditions below occurred after initiation of treatment: 
− Participant started another AED 
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− Participant increased the dose or frequency of administration of an AED ongoing at the 
time the first LCM or Active Comparator infusion started (maintenance dose of ongoing 
AED to keep target levels will be allowed) 
− Participant switched to another AED 
− Participant was administered any single dose rescue medication (eg, a BZD) for the 
treatment of ENS 
8.2 
Safety assessments 
Planned time points for all safety assessments are provided in the Schedules of Activities 
(Table 1-1 and Table 1-2). 
8.2.1 
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 study participant. 
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, 5, 
and 10 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). 
8.2.2 
Vital signs 
Vital sign measurements, including systolic blood pressure, diastolic blood pressure, pulse rate, 
respiratory rate, oxygen saturation (pulse oximetry), and body temperature, will be measured. 
8.2.3 
Physical and neurological examinations 
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. 
Clinically significant new or worsened abnormalities must be reported as AEs. 
8.2.3.1 
Sarnat score 
Physical and neurological assessments for study participants 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). 
8.2.4 
Biometric parameters 
Biometric parameters, including length, body weight, and head circumference, will be measured. 
The Baseline head circumference measurement should be taken within 7 days prior to drug 
administration, or at birth for study participants ≤7 days old. 
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8.2.5 
Electrocardiograms 
Standard 12-lead ECGs will be performed. Care should be taken to assure proper lead placement 
and quality ECG recordings.  
8.2.6 
Total blood collected 
Per guidance (Food and Drug Administration [FDA] Draft Guidance, July 2019), total blood loss 
during the study, per day, and overall, due to safety laboratory determinations, PK 
determinations, and any other blood loss including during maneuvers must be estimated and 
should be less than the maximum limit. 
Total blood volume (TBV) in a newborn is 85mL/kg. 
Total blood loss should not exceed 1% to 5% of TBV in 24 hours, and should additionally not 
exceed 3% to 10% of TBV in a month (unless local Institutional Review Boards [IRBs] have 
stricter rules). The maximum amount of blood collected from each participant over the duration 
of the study, including any extra assessments that may be required, will not exceed 17mL. 
8.2.7 
Clinical safety laboratory assessments 
See Appendix 2 (Section 10.2) for the list of clinical laboratory tests to be performed and to the 
Schedules of Activities (Table 1-1 and Table 1-2) for the timing and frequency. 
Laboratory measurements, including laboratory assessments for PDILI, will be performed by 
local laboratories unless historical data are available. Historical safety laboratory assessments, 
previously collected as StOC, may be accepted from referring hospitals as Baseline measurement 
if performed within 36 hours prior to the Treatment Period. 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless judged 
by the investigator to be more severe than expected for the participant's condition. 
If such values do not return to normal/Baseline within a period of time judged reasonable by the 
investigator, the etiology should be identified and the sponsor notified. 
All protocol-required laboratory assessments, as defined in Appendix 2 (Section 10.2), must be 
conducted in accordance with the Schedules of Activities (Table 1-1 and Table 1-2). 
If laboratory values from non-protocol specified laboratory assessments performed at the 
institution’s local laboratory require a change in participant management or are considered 
clinically significant by the investigator (eg, SAE or AE or dose modification), then the results 
must be recorded in the eCRF. 
Markedly abnormal laboratory values will be defined in the SAP. 
8.3 
Adverse events and serious adverse events 
The definitions of AE or SAE can be found in Appendix 3 (Section 10.3). 
Adverse events will be reported by a caregiver, surrogate, investigator or designee, or the 
participant's legally authorized representative. 
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The investigator and any designees are responsible for detecting, documenting, and recording 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the IMP or study procedures, or that cause the participant 
to discontinue the IMP (see Section 7). 
8.3.1 
Time period and frequency for collecting AE and SAE information 
All AEs and SAEs will be collected from the time of informed consent at the time points 
specified in the Schedules of Activities (Table 1-1 and Table 1-2). The participant will be 
monitored for AEs from the time of enrollment (consent). If the participant does not meet the 
study eligibility criteria, then the participant will be a screen failure. Adverse events leading to 
screen failure will not be counted in the study analyses. 
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 including the SFU 
Period required by the protocol, must be reported in the eCRF even if no IMP was taken but 
specific study procedures were conducted. This includes all AEs not present prior to the initial 
visit and all AEs that recurred or worsened after the initial visit. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 3 (Section 10.3). The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available. 
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 
14 days from the end of the study for each participant, and to also inform the participant’s 
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 study medication 
must be reported to UCB regardless of the time between the event and the end of the study. 
The method of recording, evaluating, and assessing causality of AE and SAE and the procedures 
for completing and transmitting SAE reports are provided in Appendix 3 (Section 10.3). 
8.3.2 
Method of detecting AEs and SAEs 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the caregiver is the preferred method to inquire about 
AE occurrences. 
8.3.3 
Follow up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AEs, SAEs, and nonserious AEs of special interest (as defined 
in Section 8.3.5), will be followed until resolution, stabilization, the investigator determines that 
it is no longer clinically significant, the event is otherwise explained, or the participant is lost to 
follow up (as defined in Section 7.3). Further information on follow-up procedures is given in 
Appendix 3 (Section 10.3). 
8.3.4 
Regulatory reporting requirements for SAEs 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
treatment under clinical investigation are met. 
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The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation. The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and investigators. 
Investigator safety reports must be prepared for suspected unexpected serious adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the IB and will notify the IRB/IEC, if appropriate according to local requirements. 
8.3.4.1 
Immediate reporting of AEs 
The following AEs must be reported immediately: 
• Serious adverse event: 
− Adverse event that the investigator classifies as serious by the definitions of SAE 
(Section 10.3) regardless of causality 
− New onset or worsening of status epilepticus after the administration of LCM 
• Infantile spasms 
• Suspected transmission of an infectious agent via a medicinal product 
• Adverse event of special interest (Section 8.3.5) 
8.3.5 
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 are LCM’s AEs of special interest: 
• The following arrhythmias: atrial fibrillation/flutter, ventricular tachycardia or fibrillation, 
AV block (second-degree Type I and II and third-degree), and marked bradycardia (<95bpm; 
Fleming et al, 2011). 
• Serious suspected multi-organ hypersensitivity reactions 
Serious suspected multi-organ hypersensitivity cases may be identified and reported to the 
sponsor by the investigator using the following algorithm as agreed with the US FDA. 
An AE or laboratory value (as defined in the following text) suggestive of internal organ 
involvement (including but not limited to hepatitis, nephritis, pneumonitis, carditis, colitis, 
encephalitis, pancreatitis, myositis, arthritis, or hematologic system involvement) combined 
with at least 1 of the following: fever, rash, lymphadenopathy, or eosinophilia. 
Treatment-emergent abnormal laboratory value criteria suggestive of internal organ 
involvement or eosinophilia: 
◦ 
Eosinophils % ≥10% 
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◦ 
Eosinophils absolute ≥0.5G/L 
◦ 
Neutrophils absolute <1.5G/L 
◦ 
Platelets ≤100G/L 
◦ 
ALT ≥2xULN  
◦ 
AST ≥2xULN 
• Potential Hy’s Law, defined as ≥3xULN ALT or AST with coexisting ≥2xULN total 
bilirubin in the absence of ≥2xULN ALP, with no alternative explanation for the biochemical 
abnormality, must ALWAYS be reported to UCB as an AE of special interest (ie, without 
waiting for any additional etiologic investigations to have been concluded). Follow-up 
information should be reported if an alternative etiology is identified during investigation and 
monitoring of the participant. 
8.4 
Safety signal detection 
Selected data from this study will be reviewed periodically to detect, as early as possible, any 
safety concern(s) related to the study medication so that investigators, clinical study participants, 
regulatory authorities, and IRBs/IECs will be informed appropriately and as early as possible. 
The Study Physician or medically qualified designee/equivalent will conduct an ongoing review 
of SAEs and perform ongoing SAE reconciliations in collaboration with the UCB PS 
representative. The DMC will be informed of the emerging safety issue and safety signals. 
As appropriate for the stage of development and accumulated experience with the study 
medication, medically qualified personnel at UCB may identify additional safety measures 
(eg, AEs, vital signs, laboratory or ECG results) for which data will be periodically reviewed 
during the course of the study. 
8.5 
Treatment of overdose 
Overdose events are only considered AEs or SAEs if there are associated clinical signs and 
symptoms or if the act of taking the excess study medication itself is an AE or SAE. 
For this study, the combined LCM dose per day should not exceed 22mg/kg. 
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. 
In the event of an overdose, the investigator should: 
1. Contact the Medical Monitor immediately. 
2. Closely monitor the participant for any AE/SAE and ECG and laboratory abnormalities until 
return to normal and for at least 3 days. 
3. Obtain a serum sample for LCM PK analysis within 3 days from the date of the last dose of 
LCM if requested by the Medical Monitor (determined on a case-by-case basis). 
4. Document the quantity of the excess dose as well as the duration of the overdose in the 
eCRF. 
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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the Medical Monitor based on the clinical evaluation of the participant. 
8.6 
Pharmacokinetics 
8.6.1 
Pharmacokinetic sampling and handling 
The time points for the collection of PK samples during the Treatment Period are described in 
Table 1-3. 
For the determination of serum concentrations of LCM, up to 7 blood microsamples (0.2mL 
sample) will be collected per study participant. Blood samples should be collected in Sarstedt 
Microvette 200 containers with conical inner tube, serum type with coagulation activator. 
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 limb 
different to that of the LCM infusion. 
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 Treatment 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 SP0968 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. 
The analysis of PK samples will be performed by liquid chromatography with tandem mass 
spectrometry at a central laboratory. 
8.6.2 
Pharmacokinetic sample shipment 
Instructions on blood sample collection, processing, storage, and labeling/shipping will be 
provided in the Laboratory Manual for this study. Appropriate storage and shipping temperatures 
will also be stated in the Laboratory Manual. 
8.6.3 
Pharmacokinetic analysis 
Measured concentrations will be introduced in the existing pediatric population PK model. After 
finalization of the study, the existing population PK model for LCM will be updated with the 
measured concentrations to further optimize the dose recommendations for LCM.  
8.7 
Genetics 
Genetics will not evaluated in this study. 
8.8 
Pharmacodynamics 
Pharmacodynamic parameters will not evaluated in this study. 
8.9 
Biomarkers 
Collection of samples for other biomarker research is not part of this study. 
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9 
STATISTICAL CONSIDERATIONS 
A description of statistical methods follows and will be described in more detail in the SAP. In 
general, descriptive summaries will be used to present the study results by treatment groups. 
9.1 
Definition of analysis sets 
Analysis sets will be defined as follows: 
• The All Participants Screened Set will consist of all study participants with a signed 
completed ICF as reported on the eCRF. 
• The Safety Set (SS) will consist of all enrolled study participants who take at least 1 dose of 
the randomized treatment. All safety analyses will be performed on the SS. 
• The Full Analysis Set (FAS) will consist of all study participants in the SS who have a 
minimum of 30 minutes of interpretable video-EEG data from both the Baseline and the first 
3 hours after randomization to the initial study medication treatment The primary analysis set 
for the efficacy data will be the FAS. 
• Per-Protocol Set (PPS) will include all participants in the FAS who did not have important 
protocol deviations related to efficacy. The secondary analysis set for the efficacy data will 
be the PPS. 
• The Pharmacokinetic Per-Protocol Set will consist of all study participants who provide at 
least 1 measurable serum sample (with recorded sampling time) on at least 1 post-Baseline 
Visit with documented study drug intake times. 
9.2 
General statistical considerations 
All statistical computations will be performed using SAS® version 9.4 or higher (SAS Institute, 
NC, USA). 
Summary statistics will consist of frequency tables for categorical variables. For continuous 
variables, descriptive statistics (will include at a minimum and where applicable the number of 
available observations, mean, median, standard deviation [SD], minimum, and maximum) will 
be tabulated. For PK parameters, the coefficient of variation and geometric mean may also be 
presented. 
9.3 
Planned efficacy analyses 
9.3.1 
Analysis of the primary efficacy endpoint 
The primary efficacy endpoint (reduction in seizure burden measured in the Evaluation 
video-EEG compared with the Baseline video-EEG; “Evaluation” is the 2-hour evaluation for 
efficacy that will start 1 hour after initiation of randomized treatment [LCM or Active 
Comparator]) will be analyzed using the Bayesian methodology at the end of the study. This will 
involve utilizing a linear model with treatment, severity, and Baseline seizure burden as variables 
and assuming normally-distributed errors. The prior distribution is vague (normal prior 
distribution with zero mean and large variance for the coefficients of the variables in the model 
and a gamma prior with a large tail for the variance of the data). The posterior distribution for 
each coefficient and for the difference between LCM and Active Comparator will be 
summarized (using means, SD, 90% credible intervals, and other summary statistics as needed). 
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The posterior probability that the difference (LCM-Active Comparator) in seizure burden is 
negative (ie, the probability that LCM is better than Active Comparator) will be presented. Other 
clinical factors that are deemed clinically important (eg, age) will be detailed in the SAP and will 
be used for a sensitivity analysis. 
Video-EEGs will be assessed locally by the investigator for any medical decisions or medical 
interventions. The final analysis of video-EEG outputs will be based solely on the assessment of 
a central reader. 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 study participant using data listings. 
9.3.2 
Analysis of the secondary efficacy endpoints 
All secondary endpoints, listed below, will be summarized descriptively. 
• Proportion of responders in the Evaluation a video-EEG compared with the Baseline 
video-EEG 
• Proportion of participants with at least 80% reduction in the Evaluation a video-EEG 
compared with the Baseline video-EEG 
• Time to response across the first 48-hours of the Treatment Period 
• Time to seizure freedom across the first 48-hours of the Treatment Period 
• Categorized percentage reduction in seizure burden in the Evaluation a video-EEG compared 
with the Baseline video-EEG (<-25% [worsening], -25% to <25% [no change], 25% to 
<50%, 50% to <80%, and ≥80%) 
• Absolute reduction in seizure burden across the first 48-hours of the Treatment Period 
• Percent reduction in seizure burden across the first 48-hours of the Treatment Period 
• Proportion of responders at the end of the first 48-hours of the Treatment Period 
• Proportion of study participants who are seizure-free (100% reduction in seizure burden from 
Baseline) at 24 hours after the start of the Treatment Period, categorized by study participants 
with nonsevere or severe seizure burden at Baseline 
a The 2-hour evaluation for efficacy will start 1 hour after initiation of randomized treatment 
(LCM or Active Comparator) and will be used for evaluation of the primary endpoint based 
on video-EEG. 
9.3.2.1 
Time to response 
Median time (in hours) to the 50% reduction in study participants with severe seizure burden or 
80% reduction in study participants with nonsevere seizure burden and the corresponding 
95% CIs will be provided based on Kaplan-Meier estimation across the first 48-hours of the 
Treatment Period. The 95% CI will be provided for descriptive purposes only. 
9.3.2.2 
Time to seizure freedom 
Median time (in hours) to seizure freedom and the corresponding 95% CIs will be provided 
based on Kaplan-Meier estimation across the first 48-hours of the Treatment Period. The 95% CI 
will be provided for descriptive purposes only. 
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9.4 
Planned safety analyses 
Descriptive summaries will be presented by the treatment groups for AEs, SAEs, physical and 
neurological examinations, laboratory results, heart rate, vital signs, body weight, and head 
circumference. Study participant 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]), rewarming status variables (duration of rewarming [date and 
start and stop time of rewarming]), and the mother’s use of AEDs (including BZD and opiates) at 
childbirth will be listed. The primary cause of seizure (eg, HIE, hemorrhage, or infarction; CNS 
malformations; CNS infections; undetermined causes) will also be used to categorize the safety 
review. 
9.5 
Planned pharmacokinetics analyses 
Summary descriptive statistics of serum concentrations will be derived per time point. 
Serum concentrations of LCM, together with demographic and other variables, will be 
introduced in the existing population PK model. The model will be used for simulating various 
dosing regimens to establish dosing recommendations as a function of developmental variables. 
The population PK analysis will be reported separately. 
9.6 
Handling of protocol deviations 
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on the key efficacy, safety, and PK outcomes for an individual study 
participant. The criteria for identifying important protocol deviations will be defined within the 
appropriate protocol-specific document. Important protocol deviations will be reviewed as part 
of the ongoing data cleaning process and data evaluation. All important deviations will be 
identified and documented prior to database lock to confirm exclusion from analysis sets. 
9.7 
Handling of dropouts or missing data 
There will be no special procedures for handling withdrawals and missing data. 
9.8 
Planned interim analysis and data monitoring 
No formal interim analysis for determination of futility or efficacy is planned for this study. To 
ensure study participant safety, periodic reviews of safety data will be performed using the 
DMC. Serious adverse events and other significant events will be monitored and triaged by the 
medical monitor and UCB PS in real time. After triage, events will be passed on to the DMC as 
appropriate. In addition, 3 reviews of safety and PK data by the DMC are planned when 25%, 
50%, and 75% of study participants have been randomized, completed, and have data available 
for evaluation, and at study completion. The objective, procedures, and timing of DMC safety 
assessments to evaluate risk and benefit for study participants in SP0968 will be described in the 
DMC Charter. 
9.8.1 
Definition of stopping rules 
No formal stopping rule will be applied. The DMC may give a recommendation to stop the study 
after reviewing the safety data as described in Section 9.8. A recommendation for stopping 
should be based on the collective experience of the DMC members. After meeting to review data 
from each treatment group, the DMC will provide a recommendation in writing regarding 
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whether to continue or to stop the study. UCB will consider this recommendation and ensure the 
study investigators are informed of the sponsor’s decision on how to continue. 
9.9 
Determination of sample size 
Randomized, controlled studies in neonatal seizures are rare, have usually been conducted with 
small to modest samples sizes and have almost exclusively focused on first-line treatment of 
neonatal seizures, usually comparing the historical standard of PB to a new intervention, 
typically either LEV or a sodium channel blocking agent such as PHT. Two major studies in 
first-line treatment of neonatal seizures have shown enormous differences in responder rates to 
PB vs LEV (80% vs 23%; NEOLEV-2 study, Sharpe et al, 2020) and to PB vs PHT (72.2% vs 
14.5%; Pathak et al, 2013) although other studies have shown smaller or no differences in studies 
with similar designs (Painter et al, 1999, Gowda et al, 2019). Only 1 randomized controlled 
study comparing different AEDs in the second-line treatment of neonatal seizures has ever been 
published (Boylan et al, 2004). In that study, 11 participants were randomized to receive either 
the sodium channel blocker lignocaine or a BZD. None of the 6 neonates on either of the 2 BZDs 
responded, but 3 of the 5 neonates on lignocaine did. 
Given the scarcity of prior evidence in randomized controlled studies in the chosen indication 
and line of treatment, this study should be considered exploratory with no formal sample size 
calculation. The chosen sample size of 32 is able to detect a treatment difference of 25% in the 
response rate with a power of 75%. 
The relationship of the efficacy metric (difference in means between the two treatment groups) 
with the related, more interpretable metric (response rate) is presented in Table 9‒1. 
Table 9‒1: 
Example of assumed responses for the two treatment groups and 
treatment effects using different metrics 
Response Assumption 
Scenario 
Difference in means 
(log(x+1)) 
Modelled difference in 
proportions (assuming Active 
Comparator Response Rate 
(RR) = 20%) 
1 
-0.82 
35% 
2 
-0.7 
30% 
3 
-0.6 
24% 
 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and ethical considerations 
The study will be conducted under the auspices of an IRB/IEC, as defined in local regulations, 
International Council for Harmonisation (ICH)-Good Clinical Practice (GCP), and in accordance 
with the ethical principles that have their origin in the Declaration of Helsinki. 
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The investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies with 
the requirements of the current ICH-GCP version or applicable country-specific regulations will 
be responsible for the initial and continuing review and approval of the clinical study. Prior to 
initiation of the study, the investigator/UCB will forward copies of the protocol, ICF, IB, 
investigator’s curriculum vitae (if applicable), advertisement (if applicable), and all other 
participant-related documents to be used for the study to the IRB/IEC for its review and 
approval. 
Before initiating a study, the investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol. 
The investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to participants or others, and any protocol deviations, to 
eliminate immediate hazards to participants. 
The investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the participants. 
For minor changes to a previously approved protocol during the period covered by the original 
approval, it may be possible for the investigator to obtain an expedited review by the IRB/IEC as 
allowed. 
As part of the IRB/IEC requirements for continuing review of approved studies, the investigator 
will be responsible for submitting periodic progress reports to the IRB/IEC (based on IRB/IEC 
requirements), at intervals appropriate to the degree of participant risk involved, but no less than 
once per year. The investigator should provide a final report to the IRB/IEC following study 
completion. 
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the investigator or the sponsor, as specified by 
the applicable regulatory requirements in each concerned country. Where applicable, 
investigators are to provide the sponsor (or its representative) with evidence of such IRB/IEC 
notification. 
10.1.2 
Financial disclosure 
Insurance coverage will be handled according to local requirements. 
Finance and insurance are addressed in the investigator and/or contract research organization 
agreements, as applicable. 
10.1.3 
Informed consent process 
Informed consent must be obtained and documented in accordance with local regulations, 
ICH-GCP requirements, and the ethical principles that have their origin in the principles of the 
Declaration of Helsinki. 
Prior to obtaining informed consent, information should be given in a language and at a level of 
complexity understandable to the participant’s parent(s) or legal representative(s) in both oral 
and written form by the investigator (or designee). Study participant’s parent(s) or legal 
representative(s) will have the opportunity to discuss the study and its alternatives with the 
investigator. 
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Prior to participation in the study, the ICF should be signed and personally dated by the 
participant’s parent(s) or legal representative(s), and by the person who conducted the informed 
consent discussion (investigator or designee). The participant’s parent(s) or legal 
representative(s) must receive a copy of the signed and dated ICF. As part of the consent process, 
each participant’s parent(s) or legal representative(s) must consent to direct access to the 
participant’s medical records for study-related monitoring, auditing, IRB/IEC review, and 
regulatory inspection. 
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 IRB/IEC and use of the amended form. 
All studies conducted at centers in the United States must include the use of a Health Insurance 
Portability and Accountability Act Authorization form. 
The participant’s parent(s) or legal representative(s) may withdraw his/her consent to participate 
in the study at any time. A participant is considered as enrolled in the study when his/her 
parent(s) or legal representative(s) has signed the ICF. An eCRF must not be started, nor may 
any study specific procedure be performed for a given participant, without having obtained 
written consent from the participant’s parent(s) or legal representative(s) to participate in the 
study. 
10.1.4 
Data protection 
UCB staff (or designee) will affirm and uphold the participant’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the participant number 
assigned at Screening. 
The investigator agrees that representatives of UCB, its designee, representatives of the relevant 
IRB/IEC, or representatives of regulatory authorities will be allowed to review that portion of the 
participant’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 participant’s study participation, and autopsy reports for deaths 
occurring during the study). 
The participant’s parent(s) or legal representative(s) must be informed that participant’s personal 
study-related data will be used by the sponsor in accordance with local data protection law. The 
level of disclosure must also be explained to the participant’s parent(s) or legal representative(s). 
The participant’s parent(s) or legal representative(s) must be informed that participant’s medical 
records may be examined by Clinical Quality Assurance auditors or other authorized personnel 
appointed by the sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.1.5 
Data quality assurance 
All participant data relating to the study will be recorded on printed or eCRF unless transmitted 
to the sponsor or designee electronically (eg, laboratory data). The investigator is responsible for 
verifying that data entries are accurate and correct by physically or electronically signing the 
eCRF. 
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The investigator must maintain accurate documentation (source data) that supports the 
information entered in the eCRF. 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and regulatory 
agency inspections and provide direct access to source data documents. 
The sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the eCRF by authorized site personnel are accurate, legible, contemporaneous, original, and 
attributable from source documents; that the safety and rights of participants are being protected; 
and that the study is being conducted in accordance with the currently approved protocol and any 
other study agreements, ICH-GCP, and all applicable regulatory requirements. 
All essential documents must be retained by the investigator for the minimum retention period 
mandatory under the applicable local laws and regulations. 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. 
Quality tolerance limits will be established for the study using parameters related to PS reporting 
and reliability of study results. The parameters will be monitored throughout the study to identify 
systematic issues. Parameters used, parameter values, important deviations from the quality 
tolerance limits, and actions taken will be summarized in the clinical study report. 
10.1.5.1 
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 eCRF. 
10.1.5.2 
Apps 
No Apps will be used in this study. 
10.1.6 
Source documents 
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). 
Source documents are original records in which raw data are first recorded. These may include 
hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, printouts, 
pharmacy records, care records, ECG or other printouts, completed scales, quality of life 
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questionnaires, or video, for example. Source documents should be kept in a secure, limited 
access area. 
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and dated 
by the investigator and become a permanent part of the participant’s source 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. 
Electronic data records, such as Holter monitor records or electroencephalogram records, must 
be saved and stored as instructed by UCB (or designee). 
10.1.7 
Study and site closure 
The sponsor designee reserves the right to close the study site or terminate the study at any time 
for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 
Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC or 
local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further study medication development 
10.1.8 
Publication policy 
The results of this study may be published or presented at scientific meetings. If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission. 
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results. In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data. In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined by mutual agreement and in line with International Committee of 
Medical Journal Editors authorship requirements. 
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10.2 
Appendix 2: Clinical laboratory tests 
• The tests detailed in the table below will be performed by the local laboratory. 
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5.1 and Section 5.1 of the protocol. 
• Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations. 
Protocol-required safety laboratory assessments 
Laboratory 
Assessments 
Parameters 
Hematology 
Platelet Count  
RBC Indices: 
MCV 
MCH 
%Reticulocytes 
WBC Count with 
Differential: 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
RBC Count 
Hemoglobin 
Hematocrit 
Clinical 
Chemistry1 
Blood Urea 
Nitrogen 
(BUN) 
Potassium 
Aspartate Aminotransferase 
(AST)/ Serum Glutamic-
Oxaloacetic Transaminase 
(SGOT) 
Total and direct 
bilirubin 
 
Creatinine 
Sodium 
Alanine Aminotransferase 
 (ALT)/ Serum Glutamic-
Pyruvic Transaminase (SGPT) 
Total Protein 
 
Glucose  
Calcium 
Alkaline phosphatase 
 
The results of each test must be entered into the eCRF. 
NOTES : 
1 Details of liver chemistry stopping criteria and required actions and follow-up assessments after liver stopping or 
monitoring event are given in Section 7.1.1 and Section 10.6. All events of ALT 3× upper limit of normal (ULN) 
and bilirubin 2× ULN (>35% direct bilirubin) or ALT 3× ULN and international normalized ratio (INR) >1.5, if 
INR measured, may indicate severe liver injury (possible Hy’s Law) and must be reported as an SAE. 
• Investigators must document their review of each laboratory safety report. 
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10.3 
Appendix 3: Adverse events – Definitions and procedures for 
recording, evaluating, follow up, and reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, temporally 
associated with the use of study medication, whether or not considered related to the study 
medication. 
• 
NOTE: An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the 
use of study medication. 
Events Meeting the AE Definition 
• 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other 
safety assessments (eg, ECG, radiological scans, vital signs measurements), including those 
that worsen from Baseline, considered clinically significant in the medical and scientific 
judgment of the investigator (ie, not related to progression of underlying disease). 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• 
New conditions detected or diagnosed after study medication administration even though it 
may have been present before the start of the study. 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study medication or 
a concomitant medication. Overdose per se will not be reported as an AE/SAE unless it is an 
intentional overdose taken with possible suicidal/self-harming intent. Such overdoses should be 
reported regardless of sequelae. 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported 
as an AE or SAE. Such instances will be captured in the efficacy assessments. However, the 
signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported as 
AE or SAE if they fulfil the definition of an AE or SAE. 
• 
The signs, symptoms, and/or clinical sequelae resulting from lack of efficacy will be reported 
as AE or SAE if they fulfil the definition of an AE or SAE. Also, "lack of efficacy" or "failure 
of expected pharmacological action" also constitutes an AE or SAE. 
Events NOT Meeting the AE Definition 
• 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments 
which are associated with the underlying disease, unless judged by the investigator to be more 
severe than expected for the participant’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the study participant’s 
condition. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that leads to the 
procedure is the AE. 
• 
Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
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• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
Definition of SAE 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an event in which the participant was at 
risk of death at the time of the event. It does not refer to an event, which hypothetically might have 
caused death, if it were more severe. 
c. Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician’s office or outpatient setting. Complications that occur during 
hospitalization are AEs. If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious. When in doubt as to whether “hospitalization” occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from Baseline is 
not considered an AE. 
d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct normal life 
functions. 
• 
This definition is not intended to include experiences of relatively minor medical significance 
such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma 
(eg, sprained ankle) which may interfere with or prevent everyday life functions but do not 
constitute a substantial disruption. 
e. Is a congenital anomaly/birth defect 
f. Important medical events: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE reporting is 
appropriate in other situations such as important medical events that may not be immediately 
life-threatening or result in death or hospitalization but may jeopardize the participant or may 
require medical or surgical intervention to prevent one of the other outcomes listed in the 
above definition. These events should usually be considered serious. 
• 
Examples of such events include, but are not limited to, potential Hy’s law, invasive or 
malignant cancers, intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
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Recording and follow up of AE and/or SAE 
AE and SAE Recording 
• 
When an AE/SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics reports) related 
to the event. 
• 
The investigator will then record all relevant AE/SAE information in the eCRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s medical records 
to UCB in lieu of completion of the AE/SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are requested by 
Regulatory Authorities. In this case, all participant identifiers, with the exception of the 
participant number, will be redacted on the copies of the medical records before submission to 
Regulatory Authorities. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. Whenever possible, the diagnosis (not the individual 
signs/symptoms) will be documented as the AE/SAE. 
Assessment of Intensity 
The investigator will make an assessment of intensity for each AE and SAE reported during the study 
and assign it to 1 of the following categories: 
• 
Mild: An event that is easily tolerated by the participant, causing minimal discomfort and not 
interfering with everyday activities. 
• 
Moderate: An event that causes sufficient discomfort and interferes with normal everyday 
activities. 
• 
Severe: An event that prevents normal everyday activities. An AE that is assessed as severe 
should not be confused with a SAE. Severe is a category utilized for rating the intensity of an 
event; and both AEs and SAEs can be assessed as severe. 
• 
An event is defined as ‘serious’ when it meets at least 1 of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe (eg, a severe AE may be 
either serious or not serious, depending on whether these criteria are also met). 
The National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE) 
should be used as a supportive standardization instrument to evaluate AEs and SAEs but the final 
intensity grading by the investigator must be mild, moderate, or severe. 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study medication and each 
occurrence of each AE/SAE. 
• 
A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or 
arguments to suggest a causal relationship, rather than a relationship cannot be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, 
as well as the temporal relationship of the event to study medication administration will be 
considered and investigated. 
• 
The investigator will also consult the investigator’s Brochure (IB) and/or Product Information, 
for marketed products, in his/her assessment. 
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• 
For each AE/SAE, the investigator must document in the medical notes that he/she has 
reviewed the AE/SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has minimal 
information to include in the initial report to the sponsor. However, it is very important that 
the investigator always make an assessment of causality for every event before the initial 
transmission of the SAE data to the sponsor. 
• 
The investigator may change his/her opinion of causality in light of follow-up information and 
send a SAE follow-up report with the updated causality assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements. 
Follow-up of AEs and SAEs 
• 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation 
with other health care professionals. 
• 
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 participant is lost to follow up. This 
follow-up requirement applies to AEs, SAEs, and AEs of special interest. 
• 
If a participant dies during participation in the study or during a recognized follow up period, 
the investigator will provide the sponsor with a copy of any post-mortem findings including 
histopathology. 
• 
New or updated information will be recorded in the originally completed eCRF. 
• 
The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt of 
the information. 
Reporting of SAEs 
SAE Reporting to UCB 
• 
If a site receives a report of a new SAE from a study participant or receives updated data on a 
previously reported SAE after the electronic data collection tool has been taken off-line, then 
the site can report this information on a paper SAE form (see next section) or to SAE 
coordinator] by telephone. 
• 
Contacts for SAE reporting can be found in Serious Adverse Event Reporting section at the 
front of the protocol. 
 
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10.4 
Appendix 4: Contraceptive guidance and collection of 
pregnancy information 
Not applicable. 
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10.5 
Appendix 5: Genetics 
Not applicable. 
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10.6 
Appendix 6: Liver safety – Suggested actions and follow-up 
assessments 
Participants with PDILI must be assessed to determine if study medication must be discontinued. 
In addition, all concomitant medications and herbal supplements that are not medically necessary 
should also be discontinued. 
Investigators should attempt to obtain information on study participants in the case of study 
medication discontinuation to complete the final evaluation. 
Study participants with PDILI should not be withdrawn from the study until investigation and 
monitoring are complete. All results of these evaluations and observations, as well as the 
reason(s) for study medication discontinuation and/or participant withdrawal (if applicable), 
must be recorded in the source documents. The eCRF must document the primary reason for 
discontinuation of study medication. 
A specific monitoring plan must be agreed between the UCB study physician and the 
investigator for study participants who have ALT >5x ULN. The monitoring plan should include 
any necessary follow-up assessments (until resolution of the abnormal lab values). 
Phase 2 liver chemistry stopping criteria are designed to assure participant safety and to evaluate 
liver event etiology. 
Liver chemistry stopping criteria 
ALT-absolute 
ALT 5xULN 
ALT Increase 
ALT 3xULN persists for 4 weeks 
Bilirubin a,b 
ALT 3xULN and bilirubin 2xULN (>35% direct bilirubin) 
INR b 
ALT 3xULN and international normalized ratio (INR) >1.5, if INR measured 
Cannot Monitor 
ALT 3xULN and cannot be monitored weekly for 4 weeks 
Symptomatic c 
ALT 3xULN associated with symptoms (new or worsening) believed to be 
related to liver injury or hypersensitivity 
Suggested actions and follow-up assessments 
Actions 
Follow-up assessments 
• 
Immediately discontinue study medication. 
• 
Report the event to the sponsor within 24 hours. 
• 
Complete the liver event electronic Case Report 
form (eCRF), and complete a serious adverse 
event (SAE) data collection tool if the event also 
met the criteria for an SAE. b 
• 
Perform liver chemistry follow-up assessments. 
• 
Viral hepatitis serology d 
• 
Obtain INR and recheck with each liver 
chemistry assessment until the 
transaminases values show downward 
trend 
• 
Obtain blood sample for pharmacokinetic 
(PK) analysis 60 minutes after the most 
recent dose e 
• 
Serum creatine phosphokinase (CPK) 
and lactate dehydrogenase (LDH) 
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Liver chemistry stopping criteria 
• 
Monitor the participant until liver chemistry test 
abnormalities resolve, stabilize, or return to 
Baseline (see MONITORING). 
• 
Do not restart/rechallenge participant with study 
medication unless allowed per protocol and 
sponsor approval is granted 
• 
If restart/rechallenge is not allowed per protocol 
or not granted, permanently discontinue study 
medication and continue the participant in the 
study for any protocol-specified follow-up 
assessmentsConsider the need for a toxicology 
screening 
 
 
MONITORING: 
If ALT 3xULN AND bilirubin 2xULN or INR 
>1.5:  
• 
Repeat liver chemistry tests (include ALT, 
aspartate transaminase [AST], alkaline 
phosphatase, bilirubin) and perform liver event 
follow-up assessments within 24 hours. 
• 
Monitor participant twice weekly until liver 
chemistry test abnormalities resolve, stabilize, or 
return to Baseline. 
• 
A specialist or hepatology consultation is 
recommended. 
If ALT 3xULN AND bilirubin <2xULN and INR 
1.5:  
• 
Repeat liver chemistry tests (include ALT, AST, 
alkaline phosphatase, bilirubin) and perform liver 
chemistry follow-up assessments within 24 to 
72 hours. 
• 
Monitor participants weekly until liver chemistry 
abnormalities resolve, stabilize, or return to 
Baseline. 
• 
Fractionate bilirubin, if total bilirubin 
2x ULN 
• 
Obtain complete blood count with 
differential to assess eosinophilia 
• 
Record the appearance or worsening of 
clinical symptoms of liver injury or 
hypersensitivity, on the adverse event 
(AE) report form 
• 
Record use of concomitant medications 
(including acetaminophen, herbal 
remedies, and other over-the-counter 
medications) on the concomitant 
medications eCRF. 
If ALT 3xULN AND bilirubin 2xULN 
or INR >1.5: 
• 
Anti-nuclear antibody, anti-smooth 
muscle antibody, Type 1 anti-liver 
kidney microsomal antibodies, and 
quantitative total immunoglobulin G 
(IgG) or gamma globulins. 
• 
Liver imaging (ultrasound, magnetic 
resonance, or computerized tomography) 
and/or liver biopsy to evaluate liver 
disease; complete liver 
a Serum bilirubin fractionation should be performed if testing is available. If serum bilirubin fractionation is not 
immediately available, discontinue study medication if ALT ≥3x ULN and bilirubin ≥2x ULN. Additionally, if 
serum bilirubin fractionation testing is unavailable, record the absence/presence of detectable urinary bilirubin 
on dipstick which is indicative of direct bilirubin elevations suggesting liver injury. 
b All events of ALT ≥3x ULN and bilirubin ≥2x ULN (>35% direct bilirubin) or ALT ≥3x ULN and INR >1.5 may 
indicate severe liver injury (possible “Hy’s Law”) and must be reported as an SAE (excluding studies of 
hepatic impairment or cirrhosis). The INR measurement is not required and the stated threshold value will not 
apply to participants receiving anticoagulants. 
c New or worsening symptoms believed to be related to liver injury (such as fatigue, nausea, vomiting, right upper 
quadrant pain or tenderness, or jaundice) or hypersensitivity (such as fever, rash, or eosinophilia). 
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d Includes: Hepatitis A immunoglobulin M (IgM) antibody; HBsAg and HBcAb; hepatitis C RNA; cytomegalovirus 
IgM antibody; Epstein-Barr viral capsid antigen IgM antibody (or if unavailable, heterophile antibody or monospot 
testing); and hepatitis E IgM antibody. 
e PK sample may not be required for participants known to be receiving Active Comparator treatment. Record the 
date/time of the PK blood sample draw and the date/time of the last dose of study medication prior to the blood 
sample draw on the eCRF. If the date or time of the last dose is unclear, provide the participant’s caregiver’s best 
approximation. If the date/time of the last dose cannot be approximated OR a PK sample cannot be collected in the 
time period indicated above, do not obtain a PK sample. Instructions for sample handling and shipping are in the 
study Laboratory Manual. 
 
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10.7 
Appendix 7: Medical device adverse events, adverse device 
effects, serious adverse events and device deficiencies: 
definition and procedures for recording, evaluating, follow up, 
and reporting 
Not applicable. 
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10.8 
Appendix 8: Rapid alert procedures 
The investigator must notify the study sponsor as soon as possible (within 24 hours of 
becoming aware of the event) by contacting the SAE Reporting info at the beginning at the 
protocol. 
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10.9 
Appendix 9: Country-specific requirements 
Not applicable. 
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10.10 
Appendix 10: Abbreviations and trademarks 
ADD 
Anticonvulsant Drug Development 
ADR 
adverse drug reaction 
AE 
adverse event 
AED 
anti-epileptic drug 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AV 
atrioventricular 
bid 
twice daily 
BZD 
benzodiazepine 
CI 
confidence interval 
CL 
clearance 
CNS 
central nervous system 
DMC 
Data Monitoring Committee 
ECG 
electrocardiogram 
eCRF 
electronic Case Report form 
ENS 
electroencephalographic neonatal seizures 
F 
bioavailability 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
CGA 
corrected gestational age 
GCP 
Good Clinical Practice 
HIE 
hypoxic-ischemic encephalopathy 
IB 
Investigator’s Brochure 
ICF 
Informed Consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
iv 
intravenous(ly) 
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LCM 
lacosamide 
LDC 
lidocaine 
LEV 
levetiracetam 
LFT 
liver function test 
MDZ 
midazolam 
NICU 
Neonatal Intensive Care Unit 
PB 
phenobarbital 
PDILI 
potential drug-induced liver injury 
PHT 
phenytoin 
PK 
pharmacokinetic(s) 
PNA 
postnatal age 
PPS 
Per-Protocol Set 
PS 
Patient Safety 
QTc 
corrected QT interval 
qxh 
every x hours 
RWE 
real world evidence 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SFU 
Safety Follow-up 
SS 
Safety Set 
StOC 
standard of care 
tid 
three times a day 
TBV 
total blood volume 
ULN 
upper limit of normal 
Vc 
distribution volume 
video-EEG 
video-electroencephalogram 
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10.11 
Appendix 11: Protocol amendment history 
Amendment 1 (13 Oct 2020) 
Overall Rationale for the Amendment 
Changes to the protocol have been made to simplify the study logistics, to update secondary 
objectives, to provide updated data from the pediatric PK model, and to improve consistency 
within the protocol. Minor grammatical, editorial, and formatting changes have also been made 
for clarification purposes only. 
Section # and Name 
Description of Change 
Brief Rationale 
1.1 Synopsis 
1.3 Schedule of activities 
3 Objectives and endpoints 
9.3.2 Analysis of the secondary 
efficacy endpoints 
9.3.2.1 Time to response 
9.3.2.2 Time to seizure freedom 
Reduce the video-EEG time 
from 96 hours to 48 hours. 
Reducing the video-EEG time 
helps to preserve the skin of the 
neonates, and allows the 
video-EEG machines to be 
available for other patients in 
the NICU. 
1.1 Synopsis 
4.1.2 Study periods 
6.3 Measures to minimize bias: 
Randomization 
11 References 
Remove the response-adaptive 
design such that all study 
participants are enrolled in a 1:1 
randomization schedule. 
Response-adaptive design works 
optimally with planned 
enrollment whereby treatment 
response is fully incorporated 
into a new randomization vector 
before the next randomization 
occurs. Given the uncertainty of 
the enrollment rate, and the 
interval between participants 
enrolling in this study, the 
randomization ratio was set at 
1:1 to ensure accurate study 
enrollment status is provided at 
the time of informed consent for 
each potential participant. 
1.1 Synopsis 
3 Objectives and Endpoints 
9.3.2 Analysis of the secondary 
efficacy endpoints 
Secondary endpoints were 
updated with 4 new endpoints:  
• 
Absolute reduction in 
seizure burden across the 
first 48-hours of the 
Treatment Period measured 
by continuous video-EEG 
compared with the Baseline 
video-EEG 
• 
Percent reduction in seizure 
burden across the first 48-
hours of the Treatment 
Period measured by 
To provide a different 
evaluation of efficacy, based on 
a reduction of seizure burden, 
rather than proportion of 
responders. 
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continuous video-EEG 
compared with the Baseline 
video-EEG 
• 
Proportion of responders at 
the end of the first 48-hours 
of the Treatment Period 
• 
Proportion of study 
participants who are seizure-
free (100% reduction in 
seizure burden from 
Baseline) at 24 hours after 
the start of the Treatment 
Period, categorized by study 
participants with nonsevere 
or severe seizure burden at 
Baseline 
9.9 Determination of sample 
size 
The following text was added:  
In addition, the sample size 
was estimated based on 
seizure count data rather than 
seizure burden (min/hour) due 
to the unavailability of the 
seizure burden data for 
neonates. 
To provide greater transparency 
in the description of the sample 
size calculation. 
1.1 Synopsis  
4.1.2 Study periods 
6.3 Measures to minimize bias: 
Randomization 
Sections updated to note that 
randomization will be stratified 
by seizure severity. 
To add clarity to the protocol. 
9.3.2.1 Time to response 
9.3.2.2 Time to seizure freedom 
The following sentence has been 
added to these sections. The 
95% CI will be provided for 
descriptive purposes only. 
To provide additional detail to 
the efficacy analyses. 
8.6.1 Pharmacokinetic sampling 
and handling 
Removal of the option to assess 
the PK of LCM using the 
commercial assay processed in 
the sites laboratory. The 
description of the analysis of the 
PK samples moved to the end of 
the section. 
The use of a central laboratory 
for all PK samples removes the 
need for cross-validation 
between laboratories, and the 
shipment of an extra sample. 
1.1 Synopsis 
3 Objectives and endpoints 
4.1.2 Study periods 
4.3 Justification for dose 
8.5 Treatment of overdose 
Text updated to confirm that 
concentrations of LCM will be 
calculated only from serum (and 
not plasma/serum). 
For accuracy in the Protocol. 
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9.1 Definition of analysis sets 
9.5 Handling of protocol 
deviations 
4.1.2 Study periods 
8.6.1 Pharmacokinetic sampling 
and handling 
The total volume of the PK 
sample has been edited from 
200μL/sample to 0.2mL/sample. 
To ensure consistency in the 
units of measurement of the PK 
sample throughout the protocol. 
2.3 Benefit/Risk Assessment 
4.3 Justification for dose 
Text updated throughout the 
section to reflect the most 
current data from the pediatric 
population PK model. 
The pediatric population PK 
model was updated. 
1.1 Synopsis 
4.1.2 Study periods 
Text updated with a revised 
LCM dose of 15mg/kg/day: A 
dose of LCM 1815mg/kg/day is 
estimated to yield approximately 
the same plasma concentrations 
as in an adult receiving LCM 
400mg/day. 
As a result of an update to the 
pediatric population PK model, 
the dose has been updated. 
Table 1-1 Schedule of Activities 
– Screening and Treatment 
Periods 
Updated the row “LCM PK 
samples” and updated Footnote 
p to indicate that PK sampling 
times are detailed in Table 1-3. 
For accuracy and consistency 
within the protocol. 
Table 1.3 Schedule for PK 
sampling 
Footnote b removed. Footnote a 
updated with preferably and 
removal of either: One optional 
sample per day, preferably 
obtained either shortly before 
dosing (trough sample) or at any 
other postdose time point (but 
never during infusion) 
To remove conflicting 
information and improve clarity. 
8.6.3 Pharmacokinetic analysis 
9.5 Planned pharmacokinetic 
analyses 
Content updated to remove the 
estimation of relevant individual 
PK parameters. 
The number of samples 
collected for PK sampling is 
sparse. With only a few samples 
per study participant, the 
estimation of individual PK 
values cannot be performed 
reliably. 
8.6.3 Pharmacokinetic analysis 
Content updated to confirm that 
data from SP0968 will be used 
to update the LCM population 
PK model at the end of the 
study. 
To distinguish the update of the 
population PK model from the 
interim review of LCM dose and 
serum concentrations during the 
study which is conducted to 
ascertain if a dose change during 
the study is required. 
1.1 Synopsis 
Figure 1-1 Schematic overview 
of the study 
Content amended to clarify that 
all study participants will enter 
the SFU period, that the SFU 
The day of the SFU visit had 
been previously omitted. Added 
for accuracy and clarity. 
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Table 1-2 Schedule of Activities 
– Extension and Safety Follow-
up Periods 
4.1.2 Study periods 
visit will occur at the end of the 
SFU period (Day 14 ± 2 days), 
and that down-titration of LCM 
dose may take place over 7 
days. 
5.2 Exclusion criteria 
Criterion #9 amended. The 
assessment of kidney function is 
to be calculated using the 
revised Schwartz formula.  
Creatinine clearance is not 
checked directly in neonatal 
infants. The Schwartz formula is 
considered the best method for 
estimating glomerular filtration 
rate in children. 
1.3 Schedule of activities 
8.2.4 HIE (Thompson score) 
9.4 Planned safety analyses 
11 References 
Removal of the Thompson score 
from the safety assessments. 
The Thompson score is not 
routinely used in NICUs. The 
Sarnat assessment which also 
assesses the severity of HIE will 
remain. 
7.1.1 Liver stopping criteria – 
potential drug-induced liver 
injury 
The PDILI criterion #2 has been 
amended, and the following 
sentence removed: 
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 
study participant may restart 
study drug after consultation 
with and approval by the 
Medical Monitor. 
Restarting study drug is not 
possible after the end of an acute 
phase of seizures. 
8.2.1 Medical history including 
Apgar score 
The following sentence has been 
amended to include 5. The score 
is reported at 1, 5 and 
10 minutes after birth 
Correction of text. 
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11 
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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:
SP0968-protocol-amend-2
Version:
1. 0
Document Number:
CLIN-000183364
Title:
SP0968 Protocol Amendment 2
Approved Date:
14 Feb 2022
Document Approvals
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 14-Feb-2022 03:18:26 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 14-Feb-2022 10:05:35 GMT+0000
Approval
Verdict: Approved
Name: 
Capacity: Clinical
Date of Signature: 14-Feb-2022 12:56:30 GMT+0000
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