Clinical trial NCT01969851
Conditions: Epilepsy
Keywords: Lacosamide Vimpat Epilepsy Children
Sponsor: UCB Pharma
Start date: 2014-02-13; Completion date: 2018-04-10
Enrollment: 55 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
SP0966 is an exploratory study to investigate safety and efficacy of Lacosamide (LCM) in children with epilepsy syndromes associated with generalized seizures. LCM will be added to current antiepileptic treatment.

Detailed description:
SP0966 is a Phase 2, multicenter, open-label exploratory study designed to assess the safety and preliminary efficacy of oral lacosamide as adjunctive therapy for epilepsy syndromes associated with generalized seizures in pediatric subjects ≥1 month to \<18 years of age.

Arms: arm 1: None
Interventions: intervention 1: Lacosamide
Intervention descriptions: intervention 1: Oral intake twice daily of tablet (100 mg or 50 mg) or syrup formulation (10 mg/ml).

Total daily dose will be titrated over a period of 6 weeks with starting dose of 100 mg/day or 2 mg/kg/day up to doses not exceeding 600 mg/day or 12 mg/kg/day tablet or syrup, respectively. Followed by a 12 week maintenance period with stable dosing of at least 200 mg/day or 4 mg/kg/day tablet or syrup, respectively.

Protocol documents:
Prot_001.pdf: 
UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 1 of 203
PROTOCOL SP0966 AMENDMENT 5
A MULTI-CENTER, OPEN-LABEL, EXPLORATORY STUDY 
TO INVESTIGATE THE SAFETY AND EFFICACY OF 
LACOSAMIDE AS ADJUNCTIVE THERAPY IN SUBJECTS 
≥1 MONTH TO <18 YEARS WITH EPILEPSY SYNDROMES 
ASSOCIATED WITH GENERALIZED SEIZURES
PHASE 2
EudraCT Number: 2012-001446-18
IND Number: 73809 (oral solution), 57939 (tablet)
Sponsor:
UCB BIOSCIENCES Inc.
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
Protocol/Amendment number
Date
Type of 
amendment
Final Protocol
30 May 2012
Not applicable
Protocol Amendment 1
19 Oct 2012
Substantial
Protocol Amendment 2
09 Nov 2012
Nonsubstantial
Protocol Amendment 3
21 Jun 2013
Substantial
Protocol Amendment 4
25 Feb 2014
Substantial
Protocol Amendment 5
26 Feb 2015
Substantial
Confidential Material
Confidential
This document is the property of UCB and may not – in full or in part – be passed 
on, reproduced, published, or otherwise used without the express permission of 
UCB.
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 2 of 203
STUDY CONTACT INFORMATION
Sponsor
UCB BIOSCIENCES Inc.
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
Principal/Coordinating Investigator
The Principal/Coordinating Investigator will be listed separately.
Sponsor Study Physician
Name:
, MD
Address:
UCB BIOSCIENCES Inc.
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
Phone:
Fax:
Clinical Project Manager 
Name:
Address:
UCB BIOSCIENCES Inc.
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
Phone:
Fax:
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 3 of 203
Clinical Trial Biostatistician 
Name:
 MA
Address:
UCB BIOSCIENCES Inc.
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
Phone:
Fax:
Clinical Monitoring Contract Research Organization
Name:
PRA Health Sciences 
Address:
4130 Park Lake Avenue, Suite 400 
Raleigh, NC 27612 
UNITED STATES
Phone:
+1 919 786 8200
Fax:
+1 919 786 8201
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 4 of 203
SERIOUS ADVERSE EVENT REPORTING
Serious adverse event reporting (24h)
Fax
Europe and Rest of the World (except Japan): +32 2 386 2421
USA: +1 800 880 6949
Canada: +1 877 582 8842
Email
Global (except Japan): DSICT@ucb.com
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 5 of 203
TABLE OF CONTENTS
LIST OF ABBREVIATIONS..................................................................................................10
1
SUMMARY.....................................................................................................................12
2
INTRODUCTION ...........................................................................................................13
3
STUDY OBJECTIVE(S).................................................................................................15
4
STUDY VARIABLES.....................................................................................................15
4.1
Safety variables......................................................................................................15
4.1.1
Primary safety variables...............................................................................15
4.1.2
Secondary safety variables...........................................................................16
4.1.3
Other variables assessing safety ..................................................................16
4.2
Preliminary efficacy variables ...............................................................................16
4.3
Pharmacokinetic and pharmacodynamic variables................................................17
5
STUDY DESIGN.............................................................................................................18
5.1
Study description ...................................................................................................18
5.1.1
Study duration per subject ...........................................................................19
5.1.2
Planned number of subjects and site(s)........................................................19
5.1.3
Anticipated regions and countries................................................................20
5.2
Schedule of study assessments...............................................................................20
5.3
Schematic diagram.................................................................................................29
5.4
Rationale for study design and selection of dose...................................................32
6
SELECTION AND WITHDRAWAL OF SUBJECTS...................................................32
6.1
Inclusion criteria ....................................................................................................32
6.2
Exclusion criteria ...................................................................................................33
6.3
Withdrawal criteria ................................................................................................35
7
STUDY TREATMENT(S) ..............................................................................................36
7.1
Description of IMP(s) ............................................................................................36
7.2
Treatment(s) to be administered ............................................................................37
7.3
Packaging...............................................................................................................40
7.4
Labeling .................................................................................................................40
7.5
Handling and storage requirements .......................................................................40
7.6
Drug accountability................................................................................................41
7.7
Procedures for monitoring subject compliance......................................................41
7.8
Concomitant medication(s)/treatment(s) ...............................................................41
7.8.1
Permitted and prohibited concomitant treatments (medications and 
therapies)......................................................................................................41
7.8.2
Rescue medication.......................................................................................42
7.9
Blinding..................................................................................................................42
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
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7.10
Randomization and numbering of subjects............................................................43
8
STUDY PROCEDURES BY VISIT ...............................................................................43
8.1
Baseline Period ......................................................................................................43
8.1.1
Visit 1 (Week -6) Screening Visit................................................................43
8.1.2
Telephone contact (Week -3).......................................................................44
8.2
Titration Period......................................................................................................44
8.2.1
Visit 2 (Day 1) .............................................................................................44
8.2.2
Telephone contacts (Weeks 1 and 3) ...........................................................46
8.2.3
Visit 3 (Week 2)...........................................................................................46
8.2.4
Visit 4 (Week 4)...........................................................................................47
8.2.5
Visit 5 (Week 5)...........................................................................................47
8.2.6
Visit 6 (Week 6, End of Titration)...............................................................47
8.3
Maintenance Period ...............................................................................................48
8.3.1
Telephone contacts (Weeks 8, 12, and 16) ..................................................48
8.3.2
Visit 7 (Week 10).........................................................................................48
8.3.3
Visit 8 (Week 14).........................................................................................49
8.3.4
Visit 9 (Week 18)/Early Termination Visit .................................................49
8.4
End of Study Period...............................................................................................51
8.4.1
Taper Period.................................................................................................51
8.4.1.1
Telephone Contact (Week 19) ...........................................................51
8.4.1.2
End of Taper Visit (Weeks 20 to 22).................................................52
8.4.2
Safety Follow-up..........................................................................................53
8.4.2.1
Safety Follow-Up Visit (Weeks 22 to 24) .........................................53
8.4.2.2
Safety Follow-Up Telephone Contact (Weeks 24 to 26)...................53
8.5
Unscheduled Visit..................................................................................................54
9
ASSESSMENT OF EFFICACY......................................................................................54
9.1
Seizure frequency...................................................................................................54
9.2
Global Impression of Change ................................................................................54
9.2.1
Clinical Global Impression of Change.........................................................54
9.2.2
Caregiver’s Global Impression of Change...................................................55
9.3
Pediatric Quality of Life Inventory........................................................................55
9.4
Health care resource use ........................................................................................55
10
ASSESSMENT OF PHARMACOKINETIC/ PHARMACODYNAMIC 
VARIABLES ...................................................................................................................55
11
ASSESSMENT OF SAFETY..........................................................................................56
11.1
Adverse events.......................................................................................................56
11.1.1
Definition of AE ..........................................................................................56
11.1.2
Procedures for reporting and recording AEs ...............................................56
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
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11.1.3
Description of AEs.......................................................................................56
11.1.4
Follow up of AEs.........................................................................................57
11.1.5
Rule for repetition of an AE ........................................................................57
11.1.6
Pregnancy.....................................................................................................57
11.1.7
Overdose of IMP..........................................................................................58
11.1.8
Safety signal detection.................................................................................58
11.2
Serious adverse events...........................................................................................58
11.2.1
Definition of SAE........................................................................................58
11.2.2
Procedures for reporting SAEs ....................................................................59
11.2.3
Follow up of SAEs.......................................................................................60
11.3
Adverse events of special interest..........................................................................60
11.4
Immediate reporting of AEs...................................................................................61
11.5
Anticipated SAEs...................................................................................................61
11.6
Laboratory measurements......................................................................................62
11.6.1
Additional laboratory tests...........................................................................62
11.6.2
Liver function tests ......................................................................................62
11.6.3
Pregnancy testing.........................................................................................63
11.7
Other safety measurements....................................................................................63
11.7.1
Seizure frequency ........................................................................................63
11.7.2
24-hour ambulatory EEG.............................................................................63
11.7.3
12-lead ECG ................................................................................................63
11.7.3.1
Overall ECG interpretation................................................................63
11.7.4
Vital signs, body weight and height.............................................................64
11.7.5
Physical examination...................................................................................64
11.7.5.1
Complete physical examination.........................................................64
11.7.5.2
Brief physical examination ................................................................64
11.7.6
Neurological examination............................................................................64
11.7.6.1
Complete neurological examination ..................................................65
11.7.6.2
Brief neurological examination..........................................................65
11.7.7
Tanner Stage ................................................................................................65
11.7.8
Achenbach CBCL........................................................................................65
11.7.9
Bayley Scales of Infant and Toddler Development, Third Edition .............66
11.7.10
Behavior Rating Inventory of Executive Function......................................66
11.7.11
Assessment of suicidality.............................................................................67
12
STUDY MANAGEMENT AND ADMINISTRATION.................................................67
12.1
Adherence to protocol............................................................................................67
12.2
Monitoring .............................................................................................................67
12.2.1
Definition of source data..............................................................................68
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 8 of 203
12.2.2
Source data verification ...............................................................................68
12.3
Data handling.........................................................................................................68
12.3.1
Case Report form completion......................................................................68
12.3.2
Database entry and reconciliation................................................................69
12.3.3
Subject Screening and Enrollment log/Subject Identification Code list......69
12.4
Termination of the study........................................................................................69
12.5
Archiving and data retention..................................................................................69
12.6
Audit and inspection ..............................................................................................70
12.7
Good Clinical Practice...........................................................................................70
13
STATISTICS ...................................................................................................................70
13.1
Definition of analysis sets......................................................................................70
13.2
General statistical considerations...........................................................................71
13.3
Planned safety analyses..........................................................................................71
13.3.1
Analysis of the primary safety variables......................................................71
13.3.2
Secondary safety variables...........................................................................71
13.3.3
Other safety analyses ...................................................................................71
13.4
Planned preliminary efficacy and other analyses...................................................72
13.4.1
Preliminary efficacy analyses ......................................................................72
13.4.2
Pharmacokinetic analyses............................................................................72
13.5
Handling of protocol deviations.............................................................................72
13.6
Handling of dropouts or missing data....................................................................72
13.7
Planned interim analysis and data monitoring.......................................................73
13.8
Determination of sample size.................................................................................73
14
ETHICS AND REGULATORY REQUIREMENTS......................................................73
14.1
Informed consent ...................................................................................................73
14.2
Subject identification cards....................................................................................74
14.3
Institutional Review Boards and IECs...................................................................74
14.4
Subject privacy.......................................................................................................75
14.5
Protocol amendments.............................................................................................75
15
FINANCE, INSURANCE, AND PUBLICATION.........................................................75
16
REFERENCES ................................................................................................................77
17
APPENDICES .................................................................................................................79
17.1
International Classification of Epileptic Seizures (1981)......................................79
17.2
Protocol Amendment 1 ..........................................................................................80
17.3
Protocol Amendment 2 ........................................................................................111
17.4
Protocol Amendment 3 ........................................................................................114
17.5
Protocol Amendment 4 ........................................................................................188
17.6
Protocol Amendment 5 ........................................................................................195
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 9 of 203
18
DECLARATION AND SIGNATURE OF INVESTIGATOR .....................................202
19
SPONSOR DECLARATION ........................................................................................203
LIST OF IN-TEXT TABLES
Table 5‒1: Schedule of study assessments (Baseline Period, Titration Period, 
Maintenance Period, End of Study Period and Unscheduled Visit).....................21
Table 7‒1: Lacosamide dose titration during the Titration Period .........................................37
Table 7‒2: Flexible LCM dosing during the Titration Period ................................................38
Table 7‒3: Required LCM dose for at least the final 3 days of Week 6.................................38
Table 7‒4: Recommended LCM dose taper for subjects <50kg receiving oral 
solution formulation..............................................................................................39
Table 7‒5: Recommended LCM dose taper for subjects ≥50kg receiving oral 
solution or tablet formulation ...............................................................................40
Table 11‒1 Anticipated SAEs for the pediatric epilepsy population.......................................61
Table 11‒2 Laboratory measurements.....................................................................................62
LIST OF IN-TEXT FIGURES
Figure 5‒1: Schematic diagram - LCM dosing and taper schedule for subjects <50kg 
receiving oral solution formulation ......................................................................30
Figure 5‒2: Schematic diagram - LCM dosing and taper schedule for subjects ≥50kg 
receiving oral solution or tablet formulation ........................................................31
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 10 of 203
LIST OF ABBREVIATIONS
AE
adverse event
AED
antiepileptic drug
ALT
alanine aminotransferase
AST 
aspartate aminotransferase
AV
atrioventricular
Bayley-III
Bayley Scales of Infant and Toddler Development®, Third Edition
bid
twice daily
BMI
body mass index
BP
blood pressure
BRIEF®-P/BRIEF®
Behavior Rating Inventory of Executive Function-Preschool Version/
Behavior Rating Inventory of Executive Function
CBCL
Child Behavior Checklist
CDMS
clinical data management system
CPMP
Committee for Proprietary Medicinal Products
CRO
contract research organization
C-SSRS
Columbia Suicide Severity Rating Scale
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic Case Report form
EEG
electroencephalogram
EI-AED
enzyme inducing antiepileptic drugs
FDA
Food and Drug Administration
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HRQoL
Health-related Quality of Life
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IRB
Institutional Review Board
iv
intravenous
IXRS
Interactive Voice/Web Response System
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 11 of 203
LCM
lacosamide
LFT
liver function test
LH
luteinizing hormone
MAO
monoamine oxidase
MedDRA
Medical Dictionary for Regulatory Activities
PedsQL™
Pediatric Quality of Life Inventory
PK 
pharmacokinetic
QTc
corrected QT interval
SAE
serious adverse event
SOP
Standard Operating Procedure
SS
Safety Set
T3
triiodothyronine
T4
thyroxine
TEAE
treatment-emergent adverse event
TSH
thyroid stimulating hormone
ULN
upper limit of normal
VNS
vagus nerve stimulation
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 12 of 203
1
SUMMARY
SP0966 is a Phase 2, multicenter, open-label exploratory study designed to assess the safety 
and preliminary efficacy of oral lacosamide (LCM, Vimpat®; SPM 927; previously referred 
to as harkoseride; [R]-2-acetamido-N-benzyl-3-ethoxypropionamide, ADD 234037) as 
adjunctive therapy for epilepsy syndromes associated with generalized seizures in pediatric 
subjects ≥1 month to <18 years of age. The objectives of this study are to evaluate the safety 
and tolerability of LCM when added to 1 to 3 concomitant antiepileptic drugs (AEDs) in 
pediatric subjects with epilepsy syndromes associated with generalized (Type II) seizures, 
and to obtain preliminary efficacy data of LCM on seizure frequency in pediatric epilepsy 
syndromes associated with generalized seizures. 
The primary variables in this study are changes in the count of generalized spike-wave 
discharges and change in days with any generalized seizures (absence, myoclonic, clonic, 
tonic, tonic-clonic, atonic, and partial evolving to secondarily generalized) from the Baseline 
Period to the Maintenance Period. The above variables reference partial seizures evolving to 
secondarily generalized seizures. While these partial seizures will be summarized as a part of 
the analysis, subjects must have a diagnosis of uncontrolled epilepsy with generalized 
seizures (Type II) according to the International Classification of Epileptic Seizures (1981) 
(see Section 17.1) to possibly be eligible for study participation. In addition to the Type II 
seizures, subjects with a current diagnosis of mixed seizure disorder(s), including both Type I 
and Type II seizures, are also eligible. Subjects with exclusively absence (Type IIA1) or 
atypical absence (Type IIA2) seizures are not eligible. Other variables to be assessed include 
measures of efficacy, plasma concentrations, and other measures of safety.
Approximately 50 subjects will be enrolled in this study across approximately 50 sites in 
Europe and North America, and other regions as deemed necessary.
The study will begin with subject screening at Visit 1 and will consist of a 6-week 
prospective Baseline Period where seizure frequency will be captured through daily seizure 
diaries. At the end of the Baseline Period, subjects will commence a 6-week Titration Period
at Visit 2, where subjects will initiate treatment with LCM (LCM dosing flexibility allowed 
based on tolerability). Subjects weighing <50kg will begin treatment on LCM oral solution 
2mg/kg/day, and subjects weighing ≥50kg will begin treatment on LCM tablets 100mg/day 
(subjects weighing ≥50kg who are unable or unwilling to swallow tablets can be dispensed 
LCM oral solution instead). The dose will be titrated to a level to optimize tolerability and 
seizure control, not to exceed 12mg/kg/day (oral solution) for subjects weighing <50kg or
600mg/day (tablets/oral solution) for subjects weighing ≥50kg. At the end of the Titration 
Period (Visit 6), a 12-week Maintenance Period will begin. Subjects must titrate to at least 
4mg/kg/day for subjects weighing <50kg or 200mg/day (tablets/oral solution) for subjects 
weighing ≥50kg in order to enter the Maintenance Period. The LCM dose will remain stable 
throughout the Maintenance Period. Subjects who require a change in dose during the 
Maintenance Period will be withdrawn from the study. Subjects who require a change in 
formulation during the Maintenance Period should consult the medical monitor to assess if 
the subject can continue in the study.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 13 of 203
The end of the Maintenance Period will be Visit 9, or, if subjects withdraw early, the Early 
Termination Visit. Subjects may be eligible for participation in an additional open-label study 
(SP848) if they have completed the Maintenance Period and are taking a minimum dose of 
4mg/kg/day for subjects weighing <50kg or 200mg/day (tablets/oral solution) for subjects 
weighing ≥50kg. Subjects who do not complete the full 12 weeks of the Maintenance Period 
may still be eligible to enter the SP848 open-label study after consultation with the medical 
monitor. Subjects who choose not to participate in the additional open-label study or subjects 
who discontinue LCM due to other reasons will enter a 2- to 4-week Taper Period followed 
by a Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM and a Safety 
Follow-Up Telephone Contact 30 days (-1/+3 days) after the final dose of LCM. Taper of 
LCM may not be required for some subjects who discontinue study medication prematurely, 
depending on the treatment option selected by the investigator in consultation with the 
subject and/or parent/legal representative.
2
INTRODUCTION
Epilepsy is the second most prevalent neurological disorder in the world. More than 
40 million people suffer from epilepsy–about 1% of the world’s population (Dichek, 1999). 
Although some forms of epilepsy may respond to surgical treatment and others may not 
require any treatment at all, most patients with epilepsy require appropriate pharmacological 
therapy (Perucca, 1996). The Institute of Medicine of the National Academies recently 
provided a review of the burdens of epilepsy, global incidence and prevalence of epilepsy, 
classification systems for seizure types and syndromes, gaps in information about epilepsy, 
and general recommendations (Institute of Medicine, 2012). Several new options for the 
medical treatment of epilepsy have been introduced, including novel AEDs and vagus nerve 
stimulation (VNS).
The classification of epilepsies in pediatric subjects was described in 1989 by the 
Commission on Classification and Terminology of the International League Against Epilepsy 
(Aicardi, 1994). Seizures are categorized based on whether the onset is focal or generalized 
and whether the disorder is idiopathic, symptomatic, or cryptogenic. Specific syndromes are 
further classified according to a number of criteria including seizure type, cause, anatomy, 
precipitating factors, age of onset, and sometimes prognosis.
The newer AEDs differ from older agents in several important ways, including mechanism of 
action, spectrum of activity, and pharmacokinetic (PK) characteristics (Herman and Pedley, 
1998). However, >30% of patients have inadequate seizure control on currently available 
AEDs or experience significant adverse drug effects (Beghi and Sander, 2008). Therefore, a 
need remains for AEDs with improved effectiveness and tolerability (Shorvon, 2009).
Among the newer AEDs, only 6 (gabapentin, lamotrigine, oxcarbazepine, topiramate, 
levetiracetam, and perampanel) have successfully demonstrated efficacy as adjunctive 
therapy in pediatric subjects with difficult to treat partial-onset seizures (Appleton et al, 1999; 
Duchowny et al, 1999; Elterman et al, 1999; Glauser et al, 2000; Glauser et al, 2006; Rheims 
and Ryvlin, 2013). Despite the availability of new AEDs, more than 25% of pediatric patients 
have inadequate seizure control on currently available AEDs or experience significant 
adverse drug effects (Hadjiloizou and Bourgeois, 2007).
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 14 of 203
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, 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’s 
mode of action is proposed to be mediated by a selective enhancement of slow inactivation of 
voltage-gated sodium channels which may explain the immediate anticonvulsant effects of 
LCM (Errington et al, 2008).
Lacosamide has been approved as adjunctive therapy in the treatment of partial-onset seizures 
with or without secondary generalization in patients 16 years of age and older in the EU (oral 
tablets, oral solution, and solution for intravenous [iv] infusion) and as adjunctive therapy in 
the treatment of partial-onset seizures in patients 17 years of age and older in the USA (oral 
tablets, oral solution, and solution for iv infusion). The oral solution and the film-coated 
tablet formulations are suitable for oral administration to pediatric patients.
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 subjects. The PK of LCM and its major metabolite, SPM 12809 
(O-desmethyl-LCM), in plasma, urine, and saliva were identical or very similar after single 
oral doses of LCM 200mg administered as tablets or as oral solution.
In the clinical development program for LCM, safety and tolerability of multiple doses of up 
to LCM 400mg bid (800mg/day) were evaluated in 868 unique subjects who received oral 
and/or iv LCM in Phase 1 studies. The safety and efficacy of LCM has also been evaluated in 
Phase 2/3 studies as adjunctive oral therapy in 1427 adult subjects with partial-onset seizures, 
as oral monotherapy in 425 adult subjects with partial-onset seizures, as adjunctive oral 
therapy in 49 subjects with primary generalized tonic-clonic seizures, and as oral 
monotherapy in 2435 adult subjects in other indications (eg, neuropathic pain, osteoarthritis, 
fibromyalgia, and migraine prophylaxis). In addition, LCM solution for infusion was 
evaluated as short-term replacement therapy in a subset of subjects with partial-onset seizures 
(199 patients) who were receiving adjunctive LCM tablets.
Three double-blind, placebo-controlled, multicenter studies (SP667, SP754, and SP755) in 
1308 adult subjects, aged 16 to 70 years, established the efficacy of oral LCM as adjunctive 
therapy (1 to 3 concomitant AEDs) in subjects with difficult to control partial-onset seizures. 
In these studies, LCM was initiated at a dose of 100mg/day (in 2 divided doses) and escalated 
to the randomized dose (200mg/day, 400mg/day, or 600mg/day) in 100mg/day per week 
increments.
When oral LCM was administered as adjunctive therapy at doses up to 600mg/day in the 
3 double-blind, placebo-controlled, multicenter studies in subjects with partial-onset seizures, 
the most frequently reported treatment-emergent adverse events (TEAEs) were central 
nervous system- and gastrointestinal-associated events. A dose relationship was seen for the 
most frequently reported common TEAEs, including dizziness, headache, nausea, and 
diplopia. The nature and frequency of adverse events (AEs) were comparable to adjunctive 
therapy with other marketed AEDs. Safety evaluations support the further development of 
LCM as an AED.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 15 of 203
UCB has completed a Phase 2, open-label safety study (SP0961) of adjunctive LCM 
treatment for primary generalized tonic-clonic seizures in 49 subjects ≥ 16 years of age with 
idiopathic generalized epilepsy. The results of SP0961 showed reductions in primary 
generalized tonic-clonic seizure frequency and myoclonic seizure days, with a small 
reduction in absence seizure days. A minority of subjects (~10%) showed an increase in 
absence seizures (reported as TEAEs) that, in this uncontrolled study, cannot be distinguished 
between the drug versus the natural course of the disease. The AE profile was similar to that 
of adjunctive LCM for the treatment of subjects with partial-onset seizures, with the 
exception of seizure-related AEs.
Further information on LCM preclinical results, as well as the PK, efficacy, and safety 
profiles, can be obtained from the current version of the LCM Investigator’s Brochure.
SP0966 is a Phase 2, multicenter, open-label exploratory study designed to assess the safety 
and preliminary efficacy of oral LCM as adjunctive therapy for epilepsy syndromes 
associated with generalized (Type II) seizures in pediatric subjects ≥1 month to <18 years of 
age.
3
STUDY OBJECTIVE(S)
•
To evaluate the safety and tolerability of LCM when added to 1 to 3 concomitant AEDs
in pediatric subjects with epilepsy syndromes associated with generalized seizures
•
To obtain preliminary efficacy data of LCM on seizure frequency in pediatric epilepsy 
syndromes associated with generalized seizures
•
An additional objective is to evaluate the PK of LCM in subjects ≥1 month to <18 years 
of age.
4
STUDY VARIABLES
The variables below reference partial seizures evolving to secondarily generalized seizures. 
While these partial seizures will be summarized as a part of the analysis, subjects must meet 
eligibility criteria to be applicable for the study (see inclusion criterion 4 and exclusion 
criteria 5 and 6 for applicable subjects).
4.1
Safety variables
4.1.1
Primary safety variables
The primary variables assessing safety are:
•
Changes in count of generalized spike-wave discharges on 24-hour ambulatory 
electroencephalogram (EEG) from Visit 2 to Visit 6 
•
Change in days with any generalized seizures (absence, myoclonic, clonic, tonic, 
tonic-clonic, atonic, partial evolving to secondarily generalized) per 28 days from the 
Baseline Period to the Maintenance Period
The assessment of seizure days will be based on the seizure diary.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 16 of 203
4.1.2
Secondary safety variables
The secondary variables assessing safety are:
•
Changes in count of 3Hz spike-wave discharges (during waking hours) on 24-hour 
ambulatory EEG from Visit 2 to Visit 6 
•
AEs as reported spontaneously by the subject and/or caregiver, or observed by the 
investigator
•
Subject withdrawals due to AEs
4.1.3
Other variables assessing safety
The other safety variables are:
•
Changes in hematology, clinical chemistry, and urinalysis parameters
•
Changes in hormone status (follicle stimulating hormone [FSH], luteinizing hormone 
[LH], triiodothyronine [T3], thyroxine [T4], thyroid stimulating hormone [TSH], and 
testosterone, as appropriate)
•
Changes in 12-lead electrocardiograms (ECGs)
•
Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate)
•
Physical and neurological examination findings
•
Changes in body weight, height, and calculated body mass index (BMI)
•
Changes in Tanner Stage (if applicable)
•
Behavioral assessment (Achenbach Child Behavior Checklist [CBCL/1½-5 or 
CBCL/6-18]) for pediatric subjects ≥18 months of age
•
Assessment of cognitive function (Behavior Rating Inventory of Executive 
Function-Preschool Version for subjects ≥2 years to <5 years of age [BRIEF®-P] or the 
Behavior Rating Inventory of Executive Function [BRIEF®] for subjects ≥5 years of age)
4.2
Preliminary efficacy variables
Variables used to assess preliminary efficacy will include:
•
Change in days with absence seizures per 28 days from the Baseline Period to the 
Maintenance Period
•
Change in days with myoclonic seizures per 28 days from the Baseline Period to the 
Maintenance Period
•
Change in days with clonic seizures per 28 days from the Baseline Period to the 
Maintenance Period 
•
Change in days with tonic seizures per 28 days from the Baseline Period to the 
Maintenance Period
•
Change in days with tonic-clonic seizures per 28 days from the Baseline Period to the 
Maintenance Period
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 17 of 203
•
Change in days with atonic seizures per 28 days from the Baseline Period to the 
Maintenance Period
•
Change in days with partial evolving to secondarily generalized seizures per 28 days from 
the Baseline Period to the Maintenance Period
•
Percent change in days with any generalized seizures (absence, myoclonic, clonic, tonic, 
tonic-clonic, atonic, partial evolving to secondarily generalized) per 28 days from the 
Baseline Period to the Maintenance Period
•
Percent change in days with absence seizures per 28 days from the Baseline Period to the 
Maintenance Period
•
Percent change in days with myoclonic seizures per 28 days from the Baseline Period to 
the Maintenance Period
•
Percent change in days with clonic seizures per 28 days from the Baseline Period to the 
Maintenance Period 
•
Percent change in days with tonic seizures per 28 days from the Baseline Period to the 
Maintenance Period
•
Percent change in days with tonic-clonic seizures per 28 days from the Baseline Period to 
the Maintenance Period
•
Percent change in days with atonic seizures per 28 days from the Baseline Period to the 
Maintenance Period
•
Percent change in days with partial evolving to secondarily generalized seizures per 
28 days from the Baseline Period to the Maintenance Period
•
Changes in count of generalized spike-wave discharges on 24-hour ambulatory EEG from 
Visit 2 to Visit 9 or at Early Termination
•
Changes in count of 3Hz spike-wave discharges (during waking hours) on 24-hour 
ambulatory EEG from Visit 2 to Visit 9 or at Early Termination
•
Clinical Global Impression of Change upon completion of the Maintenance Period
(Termination) or at Early Termination
•
Caregiver’s Global Impression of Change upon completion of the Maintenance Period
(Termination) or at Early Termination
•
Change in quality of life assessment (Pediatric Quality of Life Inventory [PedsQL™]) for 
subjects ≥1 month to ≤18 years of age
•
Health care resource use (concomitant AEDs, medical procedures, health care provider 
consultations not related to study, hospitalizations not related to study)
4.3
Pharmacokinetic and pharmacodynamic variables
Plasma concentrations of LCM and concomitant AEDs will be obtained in order to: 
•
Develop a population PK model of LCM
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 18 of 203
•
Investigate the effect of LCM on the steady-state plasma concentrations of concomitant 
AEDs
•
Investigate the correlation between LCM plasma concentrations and efficacy or safety
5
STUDY DESIGN
5.1
Study description
SP0966 is a Phase 2, multicenter, open-label exploratory study designed to assess the safety 
and preliminary efficacy of oral LCM as adjunctive therapy for epilepsy syndromes 
associated with generalized seizures in pediatric subjects ≥1 month to <18 years of age.
Subjects should have a current diagnosis of epilepsy with generalized seizures (Type II) 
according to the International Classification of Epileptic Seizures (1981), see Section 17.1. 
The diagnosis should have been established by clinical history and an EEG with generalized 
spike-wave discharges. In addition to the Type II seizures, subjects with a current diagnosis 
of mixed seizure disorder(s), including both Type I and Type II seizures, are also eligible. 
Subjects with exclusively absence (Type IIA1) or atypical absence (Type IIA2) seizures are 
not eligible. Subjects with primary generalized tonic-clonic seizures with a diagnosis of 
idiopathic generalized epilepsy are not eligible for this study as there is a confirmatory 
(Phase 3) study evaluating this seizure type.
The study treatment is LCM in either the oral solution formulation or tablet formulation. The 
formulation of LCM to be administered is based on the weight of the subject. Only subjects 
weighing ≥50kg who are able and willing to swallow tablets may be dispensed LCM tablets
(subjects weighing ≥50kg who are unable or unwilling to swallow tablets can be dispensed 
LCM oral solution instead).
Subjects will not be randomized, but all subjects who sign the informed consent form (ICF) at 
Visit 1 will be assigned a unique identification number. 
The study will begin with subject screening at Visit 1 and will consist of a 6-week 
prospective Baseline Period where seizure frequency will be captured. Subjects/caregivers 
will maintain a diary to record daily seizure activity from Visit 1 until the end of the study. 
The subject diary will capture seizure type and seizure frequency information. If all inclusion 
criteria are met and no exclusion criterion is met, the subject will begin a 6-week Titration 
Period (LCM dosing flexibility allowed based on tolerability) starting at Visit 2. Subjects will 
be asked to return to the clinic on the morning of the day prior to Visit 2 to begin 24-hour 
ambulatory EEG recordings. Subjects will initiate treatment with LCM oral solution at 
2mg/kg/day, or LCM tablets at 100mg/day based on body weight. The dose will be titrated to 
a level to optimize tolerability and seizure control, not to exceed 12mg/kg/day (oral solution) 
for subjects weighing <50kg, or 600mg/day (tablets/oral solution) in subjects weighing 
≥50kg. Subjects will increase the LCM dose in a stepwise fashion on a weekly basis to 
optimize tolerability and seizure control (see Figure 5-1 and Figure 5-2).
Lacosamide doses will be titrated according to the schedules presented in Table 7-1 and 
Table 7-2.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 19 of 203
At the end of the Titration Period (Visit 6), a 12-week Maintenance Period will begin. The 
LCM dose will remain stable throughout the Maintenance Period. Subjects who require a 
change in dose during the Maintenance Period will be withdrawn from the study. Subjects 
who require a change in formulation during the Maintenance Period should consult the 
medical monitor to assess if the subject can continue in the study.
Subjects must titrate to at least 4mg/kg/day for subjects weighing <50kg, or 
200mg/day (tablets/oral solution) for subjects weighing ≥50kg in order to enter the 
Maintenance Period. Subjects will return to the clinic (on the morning of the day prior to the 
scheduled visit) at Visit 6 and Visit 9 or Early Termination for 24-hour ambulatory EEG 
recordings for evaluation of spike-wave discharges. The end of the Maintenance Period will 
be Visit 9, or, if subjects withdraw early, the Early Termination Visit. Subjects may be 
eligible for participation in the additional open-label study (SP848) if they have completed
the Maintenance Period and are taking a minimum dose of 4mg/kg/day for subjects weighing 
<50kg, and 200mg/day (tablets/oral solution) in subjects weighing ≥50kg. Subjects who do 
not complete the full 12 weeks of the Maintenance Period may still be eligible to enter the 
SP848 open-label study after consultation with the medical monitor. Subjects who choose not 
to participate in the open-label study or subjects who discontinue due to other reasons will 
enter a 2- to 4-week Taper Period followed by a Safety Follow-Up Visit 2 weeks (±2 days) 
after the final dose of LCM and a Safety Follow-Up Telephone Contact 30 days (-1/+3 days) 
after the final dose of LCM. Dosing schedules for the Taper Period are provided in Table 7-4 
and Table 7-5. Taper of LCM may not be required for some subjects who discontinue study 
medication prematurely, depending on the treatment option selected by the investigator in 
consultation with the subject and/or parent/legal representative.
A Data Monitoring Committee (DMC) will oversee the safety of the study.
5.1.1
Study duration per subject
The duration of treatment for an individual subject may be up to approximately 18 weeks
excluding the Taper Period.
The study will consist of a 6-week prospective Baseline Period, followed by a 6-week 
Titration Period and a 12-week Maintenance Period. Subjects may be eligible to enter an 
additional open-label study (SP848) after completion of the Maintenance Period. Subjects 
who do not complete the full 12 weeks of the Maintenance Period may still be eligible to 
enter the SP848 open-label study after consultation with the medical monitor. Subjects who 
do not continue in the open-label study will enter a 2- to 4-week Taper Period followed by a 
Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM and a Safety 
Follow-Up Telephone Contact 30 days (-1/+3 days) after the final dose of LCM. The total 
study duration for a subject will be up to a maximum of 32 weeks.
The start of the study is defined as the first visit of the first subject entering the study. The 
end of the study is defined as the date of the last visit of the last subject in the study.
5.1.2
Planned number of subjects and site(s) 
Approximately 50 subjects will be enrolled. It is planned to enroll approximately 40 subjects 
between 4 years and <18 years of age and at least 10 subjects between 1 month and <4 years 
of age.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 20 of 203
5.1.3
Anticipated regions and countries
This study will be conducted at approximately 50 sites in Europe and North America, and 
other regions as deemed necessary.
5.2
Schedule of study assessments
Table 5-1 presents the tabular schedule of study procedures.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 21 of 203
Table 5‒1:
Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study 
Period and Unscheduled Visit)
Assessments
Baseline 
Period 
(6 weeks)
Treatment (18 weeks)
End of Study Period
Unsc
hed 
Visita
Titration Period (6 weeks)
Maintenance Period (12 weeks)
Taper Period 
(2-4 weeks)b
Safety 
Follow-Up 
(30 days)
Visit
V1
TC
1
V2
TC
2
V3
TC
3
V4c
V5c
End of 
Titrat
V6
TC
4
V7
TC
5
V8
TC
6
V9/
ETd
TC
7e
End 
of 
Taper 
Visitf
Safety 
FU 
Visitg
Safety 
FU 
TCg
At 
any 
time
Week in study
-6
-3
Day 
1
1
2
3
4
5
6
8
10
12
14
16
18
19
20-22
22-24
24-26
Informed consent
X
Inclusion/exclusion 
criteria
X
X
X
Medical history
X
Seizure historyh
X
EEG (24h 
monitoring)i
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant AEDs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical examination 
(complete)
X
X
X
X
Physical examination 
(brief)
X
X
X
REDACTED 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 22 of 203
Table 5‒1:
Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study 
Period and Unscheduled Visit)
Assessments
Baseline 
Period 
(6 weeks)
Treatment (18 weeks)
End of Study Period
Unsc
hed 
Visita
Titration Period (6 weeks)
Maintenance Period (12 weeks)
Taper Period 
(2-4 weeks)b
Safety 
Follow-Up 
(30 days)
Visit
V1
TC
1
V2
TC
2
V3
TC
3
V4c
V5c
End of 
Titrat
V6
TC
4
V7
TC
5
V8
TC
6
V9/
ETd
TC
7e
End 
of 
Taper 
Visitf
Safety 
FU 
Visitg
Safety 
FU 
TCg
At 
any 
time
Week in study
-6
-3
Day 
1
1
2
3
4
5
6
8
10
12
14
16
18
19
20-22
22-24
24-26
Vital signs (BP and 
pulse rate, including 
orthostatic 
assessments in 
ambulatory subjects)
X
X
X
X
X
X
X
X
X
X
X
X
Body weight and 
heightj
X
X
X
X
X
X
X
X
X
X
X
X
Head circumference
(subjects <4 years)
X
X
Neurological 
examination 
(complete)
X
X
X
X
Neurological 
examination (brief)
X
X
X
ECG (12-lead)k
X
X
X
X
X
X
X
X
X
X
Xl
Clinical chemistry/ 
hematology
X
X
X
X
Xl
X
X
Xl
Endocrinology
X
X
X
Xl
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 23 of 203
Table 5‒1:
Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study 
Period and Unscheduled Visit)
Assessments
Baseline 
Period 
(6 weeks)
Treatment (18 weeks)
End of Study Period
Unsc
hed 
Visita
Titration Period (6 weeks)
Maintenance Period (12 weeks)
Taper Period 
(2-4 weeks)b
Safety 
Follow-Up 
(30 days)
Visit
V1
TC
1
V2
TC
2
V3
TC
3
V4c
V5c
End of 
Titrat
V6
TC
4
V7
TC
5
V8
TC
6
V9/
ETd
TC
7e
End 
of 
Taper 
Visitf
Safety 
FU 
Visitg
Safety 
FU 
TCg
At 
any 
time
Week in study
-6
-3
Day 
1
1
2
3
4
5
6
8
10
12
14
16
18
19
20-22
22-24
24-26
Urinalysism
X
X
X
X
X
Xl
Pregnancy testn
X
X
X
X
X
X
X
X
X
X
X
Tanner Stageo
X
X
Concomitant AED 
plasma concentrationp
X
X
LCM plasma 
concentrationp
X
X
C-SSRSq
X
X
X
X
X
X
X
X
X
X
X
Xr
Clinical Global 
Impression of Change
X
Caregiver’s Global 
Impression of Change
X
Achenbach CBCLs
X
X
X
Bayley-IIIt
X
REDACTED 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 24 of 203
Table 5‒1:
Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study 
Period and Unscheduled Visit)
Assessments
Baseline 
Period 
(6 weeks)
Treatment (18 weeks)
End of Study Period
Unsc
hed 
Visita
Titration Period (6 weeks)
Maintenance Period (12 weeks)
Taper Period 
(2-4 weeks)b
Safety 
Follow-Up 
(30 days)
Visit
V1
TC
1
V2
TC
2
V3
TC
3
V4c
V5c
End of 
Titrat
V6
TC
4
V7
TC
5
V8
TC
6
V9/
ETd
TC
7e
End 
of 
Taper 
Visitf
Safety 
FU 
Visitg
Safety 
FU 
TCg
At 
any 
time
Week in study
-6
-3
Day 
1
1
2
3
4
5
6
8
10
12
14
16
18
19
20-22
22-24
24-26
BRIEF-P/BRIEFu
X
X
PedsQLv
X
X
Contact IXRS
X
X
X
X
X
X
X
X
X
X
Dispense LCM
Xw
X
X
X
X
X
X
Xx
LCM return
X
X
X
X
X
X
X
X
Dispense subject 
diary
X
X
X
X
X
X
X
X
Xx
Subject diary 
return/reviewy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Withdrawal criteria
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE reporting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of 
epilepsy surgery
X
VNS assessmentz
X
X
X
X
X
X
X
X
X
X
X
X
REDACTED 
D
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 25 of 203
Table 5‒1:
Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study 
Period and Unscheduled Visit)
Assessments
Baseline 
Period 
(6 weeks)
Treatment (18 weeks)
End of Study Period
Unsc
hed 
Visita
Titration Period (6 weeks)
Maintenance Period (12 weeks)
Taper Period 
(2-4 weeks)b
Safety 
Follow-Up 
(30 days)
Visit
V1
TC
1
V2
TC
2
V3
TC
3
V4c
V5c
End of 
Titrat
V6
TC
4
V7
TC
5
V8
TC
6
V9/
ETd
TC
7e
End 
of 
Taper 
Visitf
Safety 
FU 
Visitg
Safety 
FU 
TCg
At 
any 
time
Week in study
-6
-3
Day 
1
1
2
3
4
5
6
8
10
12
14
16
18
19
20-22
22-24
24-26
Health care resource 
use
X
X
X
X
X
X
X
X
X
X
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; BRIEF-P/BRIEF=Behavior Rating Inventory of Executive Function-Preschool 
Version/Behavior Rating Inventory of Executive Function; CBCL=Child Behavior Checklist; C-SSRS=Columbia Suicide Severity Rating Scale; 
ECG=electrocardiogram; EEG=electroencephalogram; ET=Early Termination; FU=Follow-Up; IXRS= interactive voice/web response system; 
LCM=lacosamide; PedsQL=Pediatric Quality of Life Inventory; TC=telephone contact; Titrat=Titration; V=Visit; VNS=vagus nerve stimulation
Note: For all visits outside of the Safety Follow-Up Period, a time window of ±2 days relative to Visit 2 (Titration Period) is applicable. The schedule above 
displays the maximum possible study duration for a subject.
a Unscheduled Visits may be performed at any time after Visit 1, at the discretion of the investigator. In addition to the required assessments indicated in the 
schedule above, the investigator can perform further assessments based on his/her clinical judgment and the medical needs of the subject (eg, assessments of 
ECG, laboratory tests, physical examination, neurological examination, etc).
b The recommended Taper Period duration is up to a maximum of 4 weeks, but a slower or faster taper may be permitted if medically necessary. The End of 
Taper Visit will occur at the end of the last week of the Taper Period.
c Visits 4 and 5 are optional and will only be required if a subject requires further LCM dose adjustment.
d At the end of Visit 9 or at ET, all subjects who complete the Maintenance Period and whose daily dose was at least 4mg/kg/day for subjects weighing <50kg, 
and 200mg/day (tablets/oral solution) for subjects weighing ≥50kg will be offered the opportunity to enroll in an additional open-label extension study, SP848.
Visit 9 or the ET Visit of SP0966 will also serve as Visit 1 for SP848. Subjects who do not complete the full 12 weeks of the Maintenance Period may still be 
eligible to enter the SP848 open-label study after consultation with the medical monitor. Subjects who do not continue in the open-label extension study will 
complete the End of Study procedures that include a 2- to 4-week LCM taper followed by a 30-day Safety Follow-Up Period. Taper of LCM may not be 
D
EF
EF-P/B
P/B
=Child 
Child 
Term
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 26 of 203
Table 5‒1:
Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study 
Period and Unscheduled Visit)
Assessments
Baseline 
Period 
(6 weeks)
Treatment (18 weeks)
End of Study Period
Unsc
hed 
Visita
Titration Period (6 weeks)
Maintenance Period (12 weeks)
Taper Period 
(2-4 weeks)b
Safety 
Follow-Up 
(30 days)
Visit
V1
TC
1
V2
TC
2
V3
TC
3
V4c
V5c
End of 
Titrat
V6
TC
4
V7
TC
5
V8
TC
6
V9/
ETd
TC
7e
End 
of 
Taper 
Visitf
Safety 
FU 
Visitg
Safety 
FU 
TCg
At 
any 
time
Week in study
-6
-3
Day 
1
1
2
3
4
5
6
8
10
12
14
16
18
19
20-22
22-24
24-26
required for some subjects who discontinue study medication prematurely, depending on the treatment option selected by the investigator in consultation with 
the subject and/or parent/legal representative.
e A telephone contact (T7) will be conducted at the end of the first week of the Taper Period.
f Each subject will have only 1 Taper Visit. The Taper Visit will be scheduled at the end of the Taper Period (Week 20, Week 21, or Week 22, depending on 
dose level achieved; see Table 7-4 and Table 7-5). A time window of ±2 days relative to Visit 2 (Titration Period) is applicable. The study week numbers 
provided are for subjects who complete the Maintenance Period and enter the Taper Period. The study week numbers provided do not apply to subjects who 
enter the Taper Period at other times.
g The Safety Follow-Up Visit will occur 2 weeks (±2 days) after the final dose of LCM. The Safety Follow-Up Telephone Contact will occur 30 days 
(-1/+3-days) after the final dose of LCM.
h Subject or caregiver (including parent/legal representative) will be asked how many seizures the subject has had over the past 4 weeks as a historical baseline.
i Ambulatory EEG to begin on the morning prior to the visit eg, the day before Visit 2, Visit 6, and Visit 9.
j Height will only be recorded at study visits where a complete physical examination is performed. Height is not required at an Unscheduled Visit.
k Two interpretable 12-lead ECG recordings will be performed approximately 20 to 30 minutes apart prior to any blood draws and vital sign assessments. The 
subject should rest in the supine position for approximately 5 minutes before the recordings and during the recordings, if possible. Recordings should be 
performed at least 15 minutes after the removal of scalp electrodes used for the 24-hour ambulatory EEG recordings at Visit 2, Visit 6, and Visit 9 or the ET 
Visit.
l The assessment will only be required for subjects with an abnormal value (clinical chemistry, hematology, or endocrinology) or reading (ECG) at the previous 
clinic visit.
REDACTED
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 27 of 203
Table 5‒1:
Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study 
Period and Unscheduled Visit)
Assessments
Baseline 
Period 
(6 weeks)
Treatment (18 weeks)
End of Study Period
Unsc
hed 
Visita
Titration Period (6 weeks)
Maintenance Period (12 weeks)
Taper Period 
(2-4 weeks)b
Safety 
Follow-Up 
(30 days)
Visit
V1
TC
1
V2
TC
2
V3
TC
3
V4c
V5c
End of 
Titrat
V6
TC
4
V7
TC
5
V8
TC
6
V9/
ETd
TC
7e
End 
of 
Taper 
Visitf
Safety 
FU 
Visitg
Safety 
FU 
TCg
At 
any 
time
Week in study
-6
-3
Day 
1
1
2
3
4
5
6
8
10
12
14
16
18
19
20-22
22-24
24-26
m For subjects aged 5 to 17 years.
n For female subjects of childbearing potential, a serum pregnancy test will be performed at Visit 1, Visit 9 or the ET Visit, and the End of Taper Visit. A serum 
pregnancy test will also be performed at the Safety Follow-Up Visit only if blood is collected for other laboratory tests. If no blood is collected for other 
assessments, then a urine pregnancy test will be performed. A urine pregnancy test will be performed at all other visits, as scheduled in Table 5-1.
o The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study.
p Blood samples for analysis of concomitant AED plasma concentrations and LCM plasma concentration will be drawn along with clinical chemistry and 
hematology samples; predose at Visit 2 and postdose at Visit 9 or the ET Visit.
q The C-SSRS will be completed for all subjects ≥6 years of age. 
r If the Unscheduled Visit is due to an AE, then the C-SSRS is required.
s The Achenbach CBCL: CBCL/1½ -5 for pediatric subjects from 18 months to 5 years 11 months and CBCL/6-18 for pediatric subjects aged 6 years and older; 
to be completed by the parent(s)/legal representative(s) (estimated completion time 45 minutes). For each subject, the same version of the scale that was 
completed at Visit 2 (CBCL/1½ -5 or CBCL/6-18) should be maintained for the duration of the study and should be completed by the same parent/legal 
representative. The same scale should be completed again by the same parent(s)/legal representative(s) later in the open-label study, SP848 (if applicable). The 
Achenbach CBCL will be used only in countries where a translated version is available.
t Bayley Scales of Infant and Toddler Development®, Third Edition for pediatric subjects <18 months of age at Baseline enrolled in English-speaking countries.
u The BRIEF-P should be used for subjects who are ≥2 years to <5 years of age at Visit 2, and the BRIEF should be used for subjects who are ≥5 years of age at 
Visit 2. The same version of the scale that was completed at Visit 2 (BRIEF-P or BRIEF) should be maintained for each subject for the duration of the study. 
The BRIEF-P and BRIEF will be used only in countries where a translated version is available.
v The version of the PedsQL used at Visit 2 should be consistent with the subject’s age at Visit 2 and should be maintained for each subject for the duration of 
REDACTED 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 28 of 203
Table 5‒1:
Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study 
Period and Unscheduled Visit)
Assessments
Baseline 
Period 
(6 weeks)
Treatment (18 weeks)
End of Study Period
Unsc
hed 
Visita
Titration Period (6 weeks)
Maintenance Period (12 weeks)
Taper Period 
(2-4 weeks)b
Safety 
Follow-Up 
(30 days)
Visit
V1
TC
1
V2
TC
2
V3
TC
3
V4c
V5c
End of 
Titrat
V6
TC
4
V7
TC
5
V8
TC
6
V9/
ETd
TC
7e
End 
of 
Taper 
Visitf
Safety 
FU 
Visitg
Safety 
FU 
TCg
At 
any 
time
Week in study
-6
-3
Day 
1
1
2
3
4
5
6
8
10
12
14
16
18
19
20-22
22-24
24-26
the study. The PedsQL will be used only in countries where a translated version is available.
w At the end of Visit 2, subjects should take the first dose of LCM in the clinic.
x For subjects entering Taper Period and not entering SP848. 
y The subject diary will be dispensed at Visit 1. At all subsequent visits, the subject and/or legal representative(s) will be reminded to complete the diary on a 
daily basis.
z As applicable, VNS assessment will only be performed for subjects with an implanted VNS device at Visit 1.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 29 of 203
5.3
Schematic diagram
Figure 5-1 presents a schematic diagram of the LCM dosing and taper schedule for subjects 
<50kg receiving the oral solution formulation, and Figure 5-2 presents a schematic diagram 
of the LCM dosing and taper schedule for subjects ≥50kg receiving the oral solution or tablet
formulation.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 30 of 203
Figure 5‒1: Schematic diagram - LCM dosing and taper schedule for subjects <50kg receiving oral solution
formulation
V1
  TC1
V2
V3-V5 and TC2-TC3
V6
V7 –V8 and TC4-T6
V9
TC7-End of Taper Visit
Baseline Period
Titration Perioda
Maintenance Periodb
Taper Periodc
12mg/kg/day 
10mg/kg/day 
8mg/kg/day 
9mg/kg/day 
Subjects
6mg/kg/day 
6mg/kg/day 
<50kg
4mg/kg/day 
4mg/kg/day 
2mg/kg/day 
2mg/kg/day 
Taper based on the maximum dose 
achieved during the Maintenance 
Period
Weeks
Week
Week
Week
Week
Week
Week
Week 7 through
Week
Week
Week
Week
-6 to 0
1
2
3
4
5
6
Week 18
19
20
21
22
TC=Telephone Contact; V=Visit 
Note: LCM dosing is designated as “mg/kg/day” 
a During Titration Period dosage may be adjusted up or down based on investigator’s clinical judgment. 
b Dose reached at the end of Titration Period will be taken throughout Maintenance Period. Subjects may be eligible for participation in the additional 
open-label study (SP848) if they have completed the Maintenance Period and are taking a minimum dose of 4mg/kg/day. Subjects will begin SP848 on the 
LCM dose they achieved in the Maintenance Period in SP0966. Subjects who do not complete the full 12 weeks of the Maintenance Period may still be eligible 
to enter the SP848 open-label study after consultation with the medical monitor.
c Subjects with doses <3mg/kg/day do not need to taper. See Table 7-5 for exact taper schedule. Taper is not required for subjects participating in the additional 
open-label study (SP848). A slower or faster taper is permitted if medically necessary. Taper of LCM may not be required for some subjects who discontinue 
study medication prematurely, depending on the treatment option selected by the investigator in consultation with the subject and/or parent/legal 
representative. The Taper Period is followed by a Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM and a Safety Follow-Up Telephone 
Contact 30 days (-1/+3 days) after the final dose of LCM.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 31 of 203
Figure 5‒2: Schematic diagram - LCM dosing and taper schedule for subjects ≥50kg receiving oral solution or 
tablet formulation
V1
  TC1
V2
V3-V5 and TC2-TC3
V6
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V9
TC7-End of Taper Visit
Baseline Period
Titration Perioda
Maintenance Periodb
Taper Periodc
600mg/day
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500mg/day
Subjects
300mg/day
300mg/day
≥50kg
200mg/day
200mg/day
100mg/day
100mg/day
Taper based on the maximum dose 
achieved during the Maintenance 
Period
Weeks
Week
Week
Week
Week
Week
Week
Week 7 through
Week
Week
Week
Week
-6 to 0
1
2
3
4
5
6
Week 18
19
20
21
22
TC=Telephone Contact; V=Visit 
Note: LCM dosing is designated as “mg/day” 
a During Titration Period dosage may be adjusted up or down based on investigator’s clinical judgment.
b Dose reached at the end of Titration Period will be taken throughout Maintenance Period. Subjects may be eligible for participation in the additional 
open-label study (SP848) if they have completed the Maintenance Period and are taking a minimum dose of 200mg/day (tablets/oral solution). Subjects will 
begin SP848 on the LCM dose they achieved in the Maintenance Period in SP0966. Subjects who do not complete the full 12 weeks of the Maintenance Period 
may still be eligible to enter the SP848 open label study after consultation with the medical monitor.
c Subjects with doses <150mg/day do not need to taper. See Table 7-5 for exact taper schedule. Taper is not required for subjects participating in the additional 
open-label study (SP848). A slower or faster taper is permitted if medically necessary. Taper of LCM may not be required for some subjects who discontinue 
study medication prematurely, depending on the treatment option selected by the investigator in consultation with the subject and/or parent/legal representative. 
The Taper Period is followed by a Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM and a Safety Follow-Up Telephone Contact 30 days 
(-1/+3 days) after the final dose of LCM.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 32 of 203
5.4
Rationale for study design and selection of dose
Epilepsy is a condition for which an improved benefit/risk ratio for medicinal products 
remains a challenge; this is especially true for pediatric patients. Based on the demonstrated 
efficacy and safety of LCM as adjunctive treatment in adult subjects with partial-onset 
seizures, and the experience with other AEDs in pediatric subjects, it is expected that LCM 
will also exhibit an acceptable benefit/risk profile in the pediatric population with 
uncontrolled generalized seizures.
In this study, the safety and tolerability of LCM will be studied when added to 1 to 
3 concomitant AEDs in pediatric subjects with epilepsy syndromes associated with 
generalized seizures. The study will also obtain preliminary efficacy data of LCM on seizure 
frequency in pediatric epilepsy syndromes associated with generalized seizures.
This study is an exploratory study to investigate on which syndromes LCM has a beneficial 
effect in order to plan confirmatory study(ies) and exclude syndromes for which LCM has no 
clear benefit or possibly induces exacerbations. 
Based on the currently available LCM pediatric safety and PK data from SP847 and SP1047, 
as well as on information available in the medical literature, the dosing recommendations for 
SP0966 are as follows:
•
Lacosamide dosing should aim to achieve LCM plasma concentrations equivalent to the 
average steady-state LCM plasma concentration reached after a LCM 200 to 600mg/day 
dose administration in adult studies.
•
A weight-based flexible dosing scheme is recommended:
−
Subjects <50kg: LCM 4-12mg/kg/day (oral solution)
−
Subjects ≥50kg: LCM 200 to 600mg/day (tablets/oral solution)
6
SELECTION AND WITHDRAWAL OF SUBJECTS
6.1
Inclusion criteria
To be eligible to participate in this study, all of the following criteria must be met:
1. A signed informed consent has been obtained from the parent/legal representative and 
assent has been obtained from the subject (when possible or as required according to local 
Institutional Review Boards [IRBs]/Independent Ethics Committees [IECs]).
2. Subject and/or caregiver (which may be a parent, a legal representative, or other 
caregiver) are willing and able to comply with all study requirements including 
maintaining a daily seizure diary.
3. Subject is male or female, ≥1 month to <18 years of age. For preterm infants <1 year old, 
the corrected gestational age should be used when determining eligibility. The generally 
accepted definition of corrected gestational age, which is calculated by subtracting the 
number of weeks born before 37 weeks of gestation from the chronological age, will be 
used for this study.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 33 of 203
4. Subject has a diagnosis of uncontrolled epilepsy with generalized seizures (Type II) 
according to the International Classification of Epileptic Seizures (1981) (see 
Section 17.1). The underlying epilepsy syndrome should be documented. Diagnosis 
should have been established by clinical history and an EEG with generalized spike-wave 
discharges. Documentation of the EEG finding of generalized spike waves (EEG 
recording or a report) is required. The EEG should have been performed no more than 
18 months prior to Visit 1 (with no change to diagnosis or seizure types during this time).
5. Subject must have experienced 2 or more events (typical generalized seizures associated 
with diagnosed epilepsy syndrome) within the 6-week prospective Baseline Period.
6. Subject is on a stable dosage regimen of 1 to 3 AEDs. The daily dosage regimen of 
concomitant AED therapy must be kept constant for a period of at least 4 weeks prior to 
the Baseline Period.
7. Vagal nerve stimulation is allowed and will not be counted as a concomitant AED. The 
VNS device must be implanted for at least 6 months before Visit 1, and the device 
settings must be stable for at least 4 weeks before Visit 1 and be kept stable during the 
Baseline Period and the Treatment Period. Use of the VNS device magnet is allowed.
8. Body weight at Visit 1 is at least 4kg for infants.
9. Females of childbearing potential must have a negative pregnancy test at Visit 1.
10. Subjects with West Syndrome are eligible if Baseline EEG demonstrates hypsarrhythmia 
despite treatment with at least 2 AEDs appropriate for the treatment of this syndrome.
6.2
Exclusion criteria
Subjects are not permitted to enroll in the study if any of the following criteria are met:
1. Subject has previously participated in this study, subject has been assigned to LCM in a 
previous LCM study, or subject has ever received LCM.
2. Subject is currently participating or has participated within the last 2 months in any study 
of an investigational drug or experimental device.
3. Subject has a history of convulsive status epilepticus within 1 month prior to Visit 1.
4. Subject has a current or previous diagnosis of pseudoseizures, conversion disorders, or 
other nonepileptic ictal events that could be confused with seizures.
5. Subject has exclusively typical absence (Type IIA1) or atypical absence (Type IIA2) 
seizures (no other generalized seizure types are reported), or has only partial-onset 
seizures (Type I).
6. Subject has primary generalized tonic-clonic seizures with a diagnosis of idiopathic 
generalized epilepsy.
7. Subject has any medical or psychiatric condition that, in the opinion of the investigator, 
could jeopardize the subject’s health or would compromise the subject’s ability to 
participate in this study.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 34 of 203
8. Subject ≥6 years of age has a lifetime history of suicide attempt (including an actual 
attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 
6 months as indicated by a positive response (“Yes”) to either Question 4 or Question 5 of 
the Columbia Suicide Severity Rating Scale (C-SSRS) at Screening.
9. Subject has a known hypersensitivity to any components of the investigational medicinal 
product (IMP). 
10. Subject has a medical condition that could reasonably be expected to interfere with drug 
absorption, distribution, metabolism, or excretion.
11. Subject has a known history of severe anaphylactic reaction or serious blood dyscrasias.
12. Subject has any history of alcohol or drug abuse within the previous 2 years. 
13. Subject has an acute or sub-acutely progressive central nervous system disease. Subject 
has epilepsy secondary to a progressing cerebral disease or any other progressively 
neurodegenerative disease (malignant brain tumor or Rasmussen Syndrome).
14. Subject has alanine aminotransferase (ALT), aspartate aminotransferase (AST), or total 
bilirubin levels ≥2x the upper limit of normal (ULN) or has alkaline phosphatase levels 
≥3x ULN.
15. Subject has impaired renal function (ie, creatinine clearance is lower than 30mL/min) at 
Visit 1.
16. Subject has sick sinus syndrome without a pacemaker, or second- or third-degree 
atrioventricular (AV) block. 
17. Subject has a clinically relevant ECG abnormality, in the opinion of the principal 
investigator (ie, second- or third-degree heart block or a corrected QT interval [QTc]
greater than 450ms).
18. Subject has hemodynamically significant heart disease (eg, heart failure).
19. Subject has an arrhythmic heart condition requiring medical therapy.
20. Subject has a known cardiac sodium channelopathy, such as Brugada syndrome. 
21. Female subject who is pregnant or nursing, and/or a female subject of childbearing 
potential who is not surgically sterile or does not practice 1 highly effective method of 
contraception (according to International Conference on Harmonisation [ICH] guidance 
defined as those that result in a failure rate of less than 1% per year when used 
consistently and correctly), unless sexually abstinent, for the duration of the study. 
Female subject of childbearing potential taking enzyme inducing antiepileptic drugs 
(EI AEDs) (carbamazepine, phenytoin, barbiturates, primidone, topiramate, 
oxcarbazepine) who is not surgically sterile or does not practice 1 highly effective method 
of contraception according to the World Health Organization recommendation (ie, depot 
medroxyprogesterone acetate, norethisterone enantate, intrauterine devices, combined 
injectables, and progestogen implants) with administration of EI-AEDs or does not 
practice 2 combined methods of contraception (ie, combined hormonal contraception plus 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 35 of 203
barrier method with spermicidal agent), unless sexually abstinent, for the duration of the 
study.
22. Subject has been treated with vigabatrin and experienced any vision loss. Subjects who 
have received vigabatrin in the past must have documentation of an assessment for vision 
loss prior to study entry or documentation of why visual field testing cannot be 
performed.
23. Subject has been treated with felbamate and has experienced any serious toxicity issues 
(defined as liver failure, aplastic anemia) with this treatment. Subjects treated with 
felbamate for less than 12 months are excluded. Note: any subject who has been treated 
with felbamate for at least 12 months and has not experienced serious toxicity issues is 
eligible.
24. Subject is taking monoamine oxidase (MAO) inhibitors or narcotic analgesics.
25. Subject is on a ketogenic or other specialized diet. If he/she was on a specialized diet in 
the past, he/she must be off the diet for at least 2 months prior to the Screening Visit
(Visit 1).
6.3
Withdrawal criteria
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care.
All subjects who withdraw from the study due to an AE must be followed until resolution of 
the event or until the event is considered stable.
Subjects must be withdrawn from the study if any of the following events occur:
1. Subject experiences intolerable AEs, including clinically relevant abnormal laboratory 
findings that, in the opinion of the investigator, preclude further participation in the study.
2. The sponsor or a regulatory agency requests withdrawal of the subject.
3. Female subject achieves menarche and does not practice contraception as provided in 
Exclusion Criterion 21, unless sexually abstinent.
4. Subject becomes pregnant, as evidenced by a positive pregnancy test.
5. Subject has QTc interval of ≥500ms that is confirmed by a cardiologist overread on any 
ECG.
6. Subject develops second- or third-degree AV block.
7. Subject is unwilling or unable to continue, or the parent/legal representative is unwilling 
or unable to allow the subject to continue in the study.
8. Investigator decides that withdrawal from further participation would be in the subject’s 
best interest. 
9. Subject has a prolongation or worsening of overall seizure duration, frequency, type, or 
pattern considered by the investigator as serious enough to warrant discontinuation from 
the study.
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 36 of 203
10. Subject uses rescue medication in excess of that permitted by the protocol.
11. Subject needs any alteration in AED daily dose or VNS settings.
12. In the case of liver function test (LFT) results of transaminases (AST, ALT, or both) 
≥3x ULN to <5x ULN and total bilirubin ≥2x ULN or transaminases (AST, ALT, or both) 
≥5x ULN, LCM must be immediately discontinued and the subject withdrawn from the 
study. The LFTs will be repeated as soon as possible, and in no case >1 week later.
13. For subjects ≥6 years of age, subject has actual suicidal ideation as indicated by a positive 
response (“Yes”) to either Question 4 or Question 5 of the “Since Last Visit” version of 
the C-SSRS. The subject should be referred immediately to a Mental Healthcare 
Professional and must be withdrawn from the study.
Subjects may be withdrawn from the study if any of the following events occur:
1. Any clinically relevant change in medical or psychiatric condition (if in the opinion of the 
investigator, the change in condition warrants discontinuation from the study).
2. Subject requires a medication that is not permitted by the protocol (see Section 7.8).
3. Subject and/or delegated caregiver is unable to manage the completion of the diary or is 
noncompliant with study procedures or medication, in the opinion of the investigator.
4. Transaminases (AST, ALT, or both) ≥3x ULN to <5x ULN, in the presence of normal 
total bilirubin, will be repeated within a few days. If the repeat testing confirms the 
abnormality (ie, transaminases are ≥3x ULN to <5x ULN with normal bilirubin), then 
weekly monitoring of LFTs should continue until resolved (ie, <3x ULN or stable 
condition). The investigator is to decide whether or not to stop LCM.
Investigators should attempt to obtain information on subjects in the case of withdrawal or 
discontinuation. For subjects considered as lost to follow up, the investigator should make an 
effort (at least 1 phone call and 1 written message to the subject), 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 subject, 
must be recorded in the source documents. The electronic Case Report form (eCRF) must
document the primary reason for withdrawal or discontinuation.
Investigators should contact the medical monitor, whenever possible, to discuss the 
withdrawal of a subject in advance.
7
STUDY TREATMENT(S)
7.1
Description of IMP(s)
The oral solution formulation contains 10mg/mL of drug substance and is colorless to pale 
yellow in appearance. Oral solution doses will be measured and administered via a dosing 
syringe. The tablet formulation will be supplied in doses of 50mg and 100mg. The 50mg 
tablets are light pink, oval, film-coated tablets debossed with “SP” on one side and “50” on 
the other. The 100mg tablets are dark yellow, oval, film-coated tablets debossed with “SP” on 
one side and “100” on the other. 
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 37 of 203
7.2
Treatment(s) to be administered
Lacosamide will be administered orally bid (at approximately 12-hour intervals in the 
morning and in the evening). Administration of oral solution by feeding tube is permitted for 
subjects who are unable to swallow the oral solution. At the end of the Baseline Period and 
completion of Visit 2, subjects who meet the eligibility criteria will commence a 6-week 
Titration Period (LCM dosing flexibility allowed based on tolerability). 
As described in Section 5.1, subjects will initiate treatment with LCM oral solution at 
2mg/kg/day, or LCM tablets at 100mg/day based on body weight. The dose will be titrated to 
a level to optimize tolerability and seizure control, not to exceed 12mg/kg/day (oral solution) 
for subjects weighing <50kg, or 600mg/day (tablets/oral solution) in subjects weighing 
≥50kg. Subjects will increase the LCM dose in a stepwise fashion on a weekly basis to 
optimize tolerability and seizure control (see Figure 5-1 and Figure 5-2). During the Titration 
Period only, back-titration is permitted.
The planned doses for each week of the Titration Period for subjects taking the LCM oral 
solution and tablet formulations are displayed in Table 7-1.
Table 7‒1:
Lacosamide dose titration during the Titration Period
Body weight 
category
(formulation)
Flexible doses for the Titration Period by study week
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
<50kg (oral 
solution)
2mg/kg/day
4mg/kg/day
6mg/kg/day
8mg/kg/day
10mg/kg/
day
12mg/kg/
day
≥50kg 
(tablets/oral 
solution)
100mg/day
200mg/day
300mg/day
400mg/day
500mg/day
600mg/day
LCM=lacosamide
Note: Subjects weighing ≥50kg who are unable or unwilling to swallow tablets can be dispensed LCM oral 
solution instead.
After completion of Week 1, investigators will assess whether a subject would tolerate a 
further dose increase or whether a subject should hold the Week 1 dose for a longer duration. 
This hold will be at the investigator’s discretion. The flexible LCM dosing over the 
remainder of the Titration Period is outlined in Table 7-2.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 38 of 203
Table 7‒2:
Flexible LCM dosing during the Titration Period
Body weight 
category 
(formulation)
Target dose 
increase/weeka
(titration)
Dose decrease per 
back-titration step
Subsequent dose increaseb
(dose increase after 
back -titration step)
Min
Max
Min
Max
<50kg (oral 
solution)
2mg/kg/day
1mg/kg/day
2mg/kg/day
1mg/kg/day
2mg/kg/day
≥50kg 
(tablets/oral 
solution)
100mg/day
50mg/day
100mg/day
50mg/day
100mg/day
LCM=lacosamide; Max=maximum; Min=minimum
a Titration step to achieve a dose not previously administered
b Titration step subsequent to a back-titration
Note: Asymmetrical dosing with no more than 50mg difference between morning and evening doses will be 
allowed for subjects taking tablets who require back-titration in a 50mg increment (ie, only 50mg and 100mg 
tablets are available)
There is no limit to the number of back-titration steps or dose holds allowed and all are at the 
investigator’s discretion; however, subjects must achieve the minimum LCM target dose for 
their body weight category by the end of the Titration Period. If it becomes apparent that a 
subject will not be able to reach the minimum target dose, then the subject should be 
withdrawn from the Titration Period and enter the Taper Period.
Subjects who have LCM titrated to a higher dose not previously administered should remain 
at that dose for ≥7 days unless a back-titration step is required based on tolerability. Subjects 
who have LCM back-titrated must remain on the lower dose for ≥3 days (in order to reach 
steady state) before a subsequent dose increase. After back-titration, subjects who return to a 
higher dose previously administered must maintain that dose for ≥3 days before subsequent 
titration to a higher dose.
As outlined in Table 7-3, subjects will be required to achieve and maintain at least a 
minimum LCM dose for at least the final 3 days of Week 6 to be eligible for entry into the 
Maintenance Period. Subjects may have a back-titration step as late as the last day of Week 6,
as long as the minimum target dose is maintained.
Table 7‒3:
Required LCM dose for at least the final 3 days of Week 6
Body weight category 
(formulation)
LCM for at least the final 3 days of Week 6
Minimum
Maximum
<50kg (oral solution)
4mg/kg/day
12mg/kg/day
≥50kg (tablets/oral solution)
200mg/day
600mg/day
LCM=lacosamide
Eligible subjects (those who reach and maintain at least the minimum LCM dose for at least 
the final 3 days of the Titration Period) will enter a 12-week Maintenance Period at the dose 
they achieved at the last day of Week 6. The LCM dose will remain stable throughout the 
Maintenance Period. Subjects who require a change in dose during the Maintenance Period 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 39 of 203
will be withdrawn from the study. Subjects who require a change in formulation during the 
Maintenance Period should consult the medical monitor to assess if the subject can continue 
in the study. Subjects may be eligible for participation in the additional open-label study 
(SP848) if they have completed the Maintenance Period and are taking a minimum dose of 
4mg/kg/day for subjects weighing <50kg, and 200mg/day (tablets/oral solution) for subjects 
weighing ≥50kg. Subjects will begin SP848 on the LCM dose they were taking in the 
Maintenance Period in SP0966. Subjects who do not complete the full 12 weeks of the 
Maintenance Period may still be eligible to enter the SP848 open-label study after 
consultation with the medical monitor.
Subjects who choose not to participate in the open-label study or subjects who discontinue
due to other reasons will enter a 2- to 4-week Taper Period followed by a Safety Follow-Up 
Visit 2 weeks (±2 days) after the final dose of LCM and a Safety Follow-Up Telephone 
Contact 30 days (-1/+3 days) after the final dose of LCM. The doses to be used during the 
Taper Period and the duration of the Taper Period will depend on the dose maintained during 
the Maintenance Period. 
Table 7-4 and Table 7-5 display the recommended LCM dose reductions during the Taper 
Period for subjects <50kg and ≥50kg, respectively. A slower taper is permitted if medically 
necessary. Whenever possible, these cases should be discussed with the medical monitor 
prior to withdrawing the subject from the study, especially in cases in which exit criteria have 
been met. In case of an emergency, a faster taper is permitted after discussion with the 
medical monitor, whenever possible. Taper of LCM may not be required for some subjects 
who discontinue study medication prematurely, depending on the treatment option selected 
by the investigator in consultation with the subject and/or parent/legal representative.
Table 7‒4:
Recommended LCM dose taper for subjects <50kg receiving oral
solution formulation
Maximum LCM dose 
achieved
Taper schedule
Week 19
Week 20
Week 21
Week 22
11-12mg/kg/day
9mg/kg/day
6mg/kg/day
4mg/kg/day
2mg/kg/day
9-10mg/kg/day
8mg/kg/day
6mg/kg/day
4mg/kg/day
2mg/kg/day
7-8mg/kg/day
6mg/kg/day
4mg/kg/day
2mg/kg/day
2mg/kg/day
5-6mg/kg/day
4mg/kg/day
2mg/kg/day
2mg/kg/day
NA
3-4mg/kg/day
2mg/kg/day
2mg/kg/day
NA
NA
LCM=lacosamide; NA=not applicable (taper not required)
Note: Subjects with doses <3mg/kg/day do not need to taper. End of Taper Visit will be at the end of Week 22 
for subjects undergoing 4 weeks of taper, at the end of Week 21 for subjects undergoing 3 weeks of taper, and at 
the end of Week 20 for subjects undergoing 2 weeks of taper.
Note: Subjects not requiring taper will enter directly into the Safety Follow-Up Period and not attend any Taper 
Period visits.
Note: The study week numbers provided are for subjects who complete the Maintenance Period and enter the 
Taper Period. The study week numbers provided do not apply to subjects who enter the Taper Period at other 
times.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 40 of 203
Table 7‒5:
Recommended LCM dose taper for subjects ≥50kg receiving oral 
solution or tablet formulation
Maximum LCM 
dose maintained
Taper schedule
Week 19
Week 20
Week 21
Week 22
550-600mg/day
500mg/day
300mg/day
200mg/day
100mg/day
450-500mg/day
400mg/day
300mg/day
200mg/day
100mg/day
350-400mg/day
300mg/day
200mg/day
100mg/day
100mg/day
250-300mg/day
200mg/day
100mg/day
100mg/day
NA
150-200mg/day
100mg/day
100mg/day
NA
NA
LCM=lacosamide; NA=not applicable (taper not required)
Note: Subjects with doses <150mg/day do not need to taper. End of Taper Visit will be at the end of Week 22 
for subjects undergoing 4 weeks of taper, at the end of Week 21 for subjects undergoing 3 weeks of taper, and at 
the end of Week 20 for subjects undergoing 2 weeks of taper.
Note: Subjects not requiring taper will enter directly into the Safety Follow-Up Period and not attend any Taper 
Period visits.
Note: The study week numbers provided are for subjects who complete the Maintenance Period and enter the 
Taper Period. The study week numbers provided do not apply to subjects who enter the Taper Period at other 
times.
7.3
Packaging
Lacosamide is manufactured, packaged, and labeled according to Good Manufacturing 
Practice (GMP) guidelines and applicable laws or regulations. It is suitably packaged in such 
a way as to protect the product from deterioration during transport and storage.
Lacosamide tablets will be packaged in high-density polyethylene bottles with a child-proof 
polypropylene screw cap. The oral solution will be packaged in amber polyethylene 
terephthalate bottles with a white, child-proof, polypropylene screw cap.
7.4
Labeling
Clinical drug supplies will be labeled in accordance with the current ICH guidelines on Good 
Clinical Practice (GCP) and GMP and will include any locally required statements. If 
necessary, labels will be translated into the local language.
7.5
Handling and storage requirements
The investigator (or designee) is responsible for the safe and proper storage of IMP at the 
site. Investigational medicinal product stored by the investigator is to be kept in a secured 
area with limited access.
Lacosamide is to be stored according to the instructions on the label. Lacosamide is stable at 
room temperature and is to be stored at temperatures not exceeding 25°C (77°F). Lacosamide 
should not be refrigerated or frozen.
Appropriate storage conditions must be ensured either by controlled room temperature, or by 
completion of a temperature log (showing minimum and maximum temperatures reached 
over the time interval) in accordance with local requirements on a regular basis. Data should 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 41 of 203
be available to support the temperature conditions maintained at the clinical site (eg manual 
temperature logs or automated chart recordings).
In case an out of range temperature is noted, it must be immediately communicated to the 
sponsor’s designee in accordance with the pharmacy manual.
The investigator (or designee) will instruct the subject to store the IMP following the 
instructions on the label.
7.6
Drug accountability
A Drug Accountability form will be used to record IMP dispensing and return information on 
a by-subject basis and will serve as source documentation during the course of the study. 
Details of any IMP lost (due to breakage or wastage), not used, or returned to the sponsor’s
designee must also be recorded on the appropriate forms. All supplies and pharmacy 
documentation must be made available throughout the study for UCB (or designee) to review.
The investigator (or designee) is responsible for retaining all used, unused, and partially used 
containers of IMP until returned.
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 period of the study, all used (including 
empty containers) and unused IMP containers must be reconciled and returned to UCB’s
designee, preferably in their original package. Investigational medicinal product intended for 
the study cannot be used for any other purpose than that described in this protocol.
7.7
Procedures for monitoring subject compliance
At each visit after IMP is dispensed, subjects must return all used, unused, and empty IMP
containers. Drug accountability must be done in the subject’s presence in order to obtain 
explanations regarding discrepancies in compliance with the dosing regimen. Drug 
accountability must be recorded on the Drug Accountability form.
If a subject is found to be persistently noncompliant (defined as <75% or >125% compliant 
with the dosage schedule), the sponsor, in conjunction with the investigator, will make a 
decision as to whether the subject should be withdrawn from the study.
7.8
Concomitant medication(s)/treatment(s)
7.8.1
Permitted and prohibited concomitant treatments (medications 
and therapies)
Subject must have been maintained on a stable dose regimen of 1 to 3 marketed AEDs for at 
least 4 weeks prior to Visit 1 (ie, prior to entry into the Baseline Period); the dose regimen of 
the AEDs must be kept stable through the end of the Maintenance Period.
Vagal nerve stimulation is allowed and will not be counted as a concomitant AED. The VNS 
device must be implanted for at least 6 months before Visit 1, and the device settings must be 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 42 of 203
stable for at least 4 weeks before Visit 1 and be kept stable during the Baseline Period and 
through the end of the Maintenance Period.
The following medications/therapies are prohibited during the course of this study:
•
Neuroleptics
•
MAO inhibitors
•
Barbiturates (except as anti-epileptic medications)
•
Narcotic analgesics
Subjects who have been treated with vigabatrin and experienced any vision loss are excluded 
from the study. Subjects who have received vigabatrin in the past must have documentation 
of an assessment for vision loss prior to study entry or documentation of why visual field 
testing cannot be performed.
Subjects who have been treated with felbamate and have experienced any serious toxicity 
issues (defined as liver failure, aplastic anemia) with this treatment are excluded from the 
study. Subjects treated with felbamate for less than 12 months are also excluded. Any subject 
who has been treated with felbamate for at least 12 months and has not experienced serious 
toxicity issues is eligible for the study.
The following medications are not allowed unless used as described:
•
Amphetamines and sedative antihistamines: stable use only.
•
Anxiolytics or once-daily hypnotics: stable, low doses are allowed for nonepilepsy 
indications only.
The chronic use of benzodiazepines is allowed for treatment of epilepsy. Benzodiazepines 
taken for treatment of epilepsy will be counted as 1 of the AEDs, and the dose regimen must 
be stable for ≥28 days prior to Visit 1. Intermittent use of benzodiazepines as rescue therapy 
for epilepsy is allowed if taken at a maximum frequency of 1 day per week (with up to 
3 doses within 24 hours).
Therapy that becomes necessary (in the investigator’s opinion) during the course of the study 
must not be refused to a subject, even if described above as a therapy that is expressly not 
permitted. In cases where this occurs but withdrawal criteria have not been met, the 
advisability of the subject’s continuation in the study must be discussed between the medical 
monitor and the investigator.
7.8.2
Rescue medication
The use of benzodiazepines as rescue therapy for epilepsy is allowed if taken at a maximum 
frequency of 1 day per week (with up to 3 doses within 24 hours) during study participation; 
more frequent use precludes subjects from study participation.
7.9
Blinding
SP0966 is an open-label study; thus, there will be no blinding.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 43 of 203
7.10
Randomization and numbering of subjects
Subjects will not be randomized in this study. A unique 5-digit identification number will be 
assigned by an Interactive Voice/Web Response System (IXRS) to all subjects who sign the 
ICF at Visit 1. This subject number will be used to identify the subject throughout the study 
and to maintain subject confidentiality. At subsequent visits, the IXRS will assign the 
applicable LCM bottle number. Further instructions will be provided in the IXRS manual.
8
STUDY PROCEDURES BY VISIT
All visits occur at the end of the respective week in the study; a window of ±2 days relative to 
Visit 2 is applicable for all visits and telephone contacts.
A detailed tabular schedule of study procedures is provided in Section 5.2.
8.1
Baseline Period
8.1.1
Visit 1 (Week -6) Screening Visit
At Visit 1, subjects will be evaluated for their suitability for enrollment. The Screening Visit 
assessments will be conducted 6 weeks prior to the first administration of LCM. It is 
acceptable for the Screening assessments to be conducted over >1 day. Prior to the conduct of 
any study-related procedures, a complete explanation (both verbal and written) of the nature 
and purpose of the study will be given to the subject (when possible or as required according 
to local IRBs/IECs) and the subject’s parent/legal representative by the investigator (or 
designee). The subject’s parent/legal representative will be requested to sign and date the 
IRB/IEC-approved ICF. When possible, or as required by the local IRB/IEC, the subject will 
be requested to give assent to participate in the study.
The subject’s eligibility for the study will be determined on the basis of the 
inclusion/exclusion criteria, signature on an ICF prior to any study-related procedures or 
evaluations, and the results of the following pretreatment assessments (for further details of 
the assessments and the required procedures and methods, please refer to Section 9 and 
Section 11 of this protocol):
•
Contact IXRS to obtain unique subject identification number.
•
Review seizure history. The subject or caregiver (including parent/legal representative) 
will be asked how many seizures the subject has had over the past 4 weeks as a historical 
Baseline.
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Medical history assessment.
•
Complete physical examination.
•
Complete neurological examination.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 44 of 203
•
12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed prior to 
any blood draws and vital signs assessment and, if possible, with the subject in the supine 
position for approximately 5 minutes preceding the recordings and during the recordings).
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory subjects).
•
Body weight and height assessment.
•
Head circumference in subjects <4 years of age.
•
Epilepsy surgery assessment.
•
C-SSRS (if applicable). The C-SSRS will be completed for all subjects ≥6 years of age.
•
Blood sample for clinical chemistry, hematology, and endocrinology.
•
Serum pregnancy test (if applicable).
•
Urine sample for urinalysis (if applicable). Will be performed for subjects aged 5 to 
17 years.
•
Tanner Stage (if applicable). The Tanner Stage will be performed only for subjects who 
are pubescent at Visit 1 or who enter puberty during the course of the study.
•
Dispense subject diary and remind subject to complete subject diary on a daily basis.
•
AE reporting.
Eligible subjects will be scheduled to return to the clinic (Visit 2, Day 1) approximately 
6 weeks ±2 days after the Screening Visit.
8.1.2
Telephone contact (Week -3)
Three weeks before Visit 2 (±2 days), the investigator or designee should contact the 
subject’s caregiver (including parent/legal representative) by telephone. The investigator (or 
designee) should remind the subject’s caregiver (including parent/legal representative) to 
ensure the diary is completed. The following should be performed via telephone:
•
Review inclusion/exclusion criteria
•
Concomitant medications assessment
•
Concomitant AEDs assessment
•
Reminder to complete subject diary on a daily basis
•
Review withdrawal criteria
•
AE reporting
8.2
Titration Period
8.2.1
Visit 2 (Day 1)
Subjects will be asked to return to the clinic on the morning of the day prior to Visit 2 (end of 
Week 0) to begin 24-hour ambulatory EEG recordings. Scalp electrodes will be attached, and 
subjects will receive a recording device. Subjects will be asked to return approximately 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 45 of 203
24 hours later (for Visit 2, Day 1) for removal of the scalp electrodes and return of the 
recording device. At Visit 2, the investigator should determine whether the subject is still 
eligible and willing to continue in the study. 
The following will be performed prior to the first dose of LCM:
•
Review inclusion/exclusion criteria.
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Complete physical examination.
•
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•
12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed prior to 
any blood draws and vital signs assessment and, if possible, with the subject in the supine 
position for approximately 5 minutes preceding the recordings and during the recordings. 
Recordings should be performed at least 15 minutes after removal of scalp electrodes 
used for the 24-hour ambulatory EEG recording).
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory subjects).
•
Body weight and height assessment.
•
C-SSRS (if applicable).
•
Blood sample for clinical chemistry and hematology.
•
Blood sample for LCM and concomitant AED plasma concentrations (before dosing with 
LCM). Blood sample will be drawn along with clinical chemistry and hematology 
samples.
•
Achenbach CBCL (if applicable); CBCL/1½-5 or CBCL/6-18 for pediatric subjects
≥18 months of age.
•
Bayley Scales of Infant and Toddler Development®, Third Edition (Bayley-III Scales) (if 
applicable). For pediatric subjects <18 months of age at Baseline enrolled in 
English-speaking countries. 
•
BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) (version consistent with 
age at the visit).
•
PedsQL for subjects ≥1 month to ≤18 years of age (version consistent with age at the 
visit).
•
Urine sample for urinalysis (if applicable).
•
Urine pregnancy test (if applicable).
•
Subject diary return/review.
•
AE reporting.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 46 of 203
•
Review withdrawal criteria.
•
Contact IXRS.
•
Dispense subject diary.
•
Reminder to complete subject diary on a daily basis.
•
Health care resource use.
•
Dispense LCM. Subjects should take the first dose of LCM (based on body weight) in the 
clinic. The starting dose for subjects taking the oral solution formulation will be 
2mg/kg/day, and the starting dose for subjects taking the tablet formulation will be 
100mg/day.
8.2.2
Telephone contacts (Weeks 1 and 3)
At the end of Weeks 1 and 3 (±2 days), the investigator or designee should contact the 
subject’s caregiver (including parent/legal representative) by telephone. The assessments for 
these telephone contacts are the same as those performed during the telephone contact at 
Week -3 in Section 8.1.2 with the exception that inclusion/exclusion criteria do not need to be 
checked at Weeks 1 and 3.
8.2.3
Visit 3 (Week 2)
At Visit 3 (end of Week 2 ±2 days), subjects will return for a clinic visit, and the following 
will be performed:
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory subjects).
•
Body weight assessment.
•
Urine pregnancy test (if applicable)
•
C-SSRS (if applicable).
•
12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed prior to 
any blood draws and vital signs assessment and, if possible, with the subject in the supine 
position for approximately 5 minutes preceding the recordings and during the recordings).
•
Subject diary return/review.
•
LCM return.
•
AE reporting.
•
Review withdrawal criteria.
•
Contact IXRS.
•
Dispense subject diary.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 47 of 203
•
Reminder to complete subject diary on a daily basis.
•
Health care resource use.
•
Dispense LCM.
8.2.4
Visit 4 (Week 4)
Assessments for Visit 4 (end of Week 4 ±2 days) are the same as those described for Visit 3 
(end of Week 2) in Section 8.2.3. This visit is optional and will only be required if a subject 
requires further LCM dose adjustment.
8.2.5
Visit 5 (Week 5)
Assessments for Visit 5 (end of Week 5 ±2 days) are the same as those described for Visit 3 
(end of Week 2) in Section 8.2.3. This visit is optional and will only be required if a subject 
requires further LCM dose adjustment.
8.2.6
Visit 6 (Week 6, End of Titration)
Subjects will be asked to return to the clinic on the morning of the day prior to Visit 6 (end of 
Week 6 ±2 days) to begin 24-hour ambulatory EEG recordings. Scalp electrodes will be 
attached, and subjects will receive a recording device. Subjects will be asked to return 
approximately 24 hours later (for Visit 6) for removal of the scalp electrodes and return of the 
recording device.
At Visit 6 (end of Week 6), subjects will return for a clinic visit, and the following will be 
performed:
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Brief physical examination.
•
Brief neurological examination.
•
12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed prior to 
any blood draws and vital signs assessment and, if possible, with the subject in the supine 
position for approximately 5 minutes preceding the recordings and during the recordings. 
Recordings should be performed at least 15 minutes after removal of scalp electrodes 
used for the 24-hour ambulatory EEG recording). 
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory subjects).
•
Body weight assessment.
•
C-SSRS (if applicable).
•
Blood sample for clinical chemistry and hematology.
•
Urine sample for urinalysis (if applicable).
•
Urine pregnancy test (if applicable).
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 48 of 203
•
Achenbach CBCL (if applicable); CBCL/1½-5 or CBCL/6-18 for pediatric subjects 
≥18 months of age (same version that was used at Visit 2).
•
Subject diary return/review.
•
LCM return.
•
AE reporting.
•
Review withdrawal criteria.
•
Contact IXRS.
•
Dispense subject diary.
•
Reminder to complete subject diary on a daily basis.
•
Health care resource use.
•
Dispense LCM for the first 4 weeks of the Maintenance Period.
8.3
Maintenance Period 
8.3.1
Telephone contacts (Weeks 8, 12, and 16)
At the end of Weeks 8, 12, and 16 (±2 days), the investigator or designee should contact the 
subject’s caregiver (including parent/legal representative) by telephone. The assessments for 
these telephone contacts are the same as those performed during the telephone contact at 
Week -3 in Section 8.1.2 with the exception that inclusion/exclusion criteria do not need to be 
checked at Weeks 8, 12, and 16.
Subjects must titrate to at least 4mg/kg/day for subjects weighing <50kg, or 
200mg/day (tablets/oral solution) for subjects weighing ≥50kg in order to enter the 
Maintenance Period.
8.3.2
Visit 7 (Week 10)
At Visit 7 (end of Week 10 ±2 days), subjects will return for a clinic visit, and the following 
will be performed:
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory subjects).
•
Body weight assessment.
•
12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed prior to 
any blood draws and vital signs assessment and, if possible, with the subject in the supine 
position for approximately 5 minutes preceding the recordings and during the recordings).
•
C-SSRS (if applicable).
•
Blood sample for clinical chemistry and hematology.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 49 of 203
•
Urine pregnancy test (if applicable).
•
Subject diary return/review.
•
LCM return.
•
AE reporting.
•
Review withdrawal criteria.
•
Contact IXRS.
•
Dispense subject diary.
•
Reminder to complete subject diary on a daily basis.
•
Health care resource use.
•
Dispense LCM.
8.3.3
Visit 8 (Week 14)
Assessments for Visit 8 (end of Week 14 ±2 days) are the same as those described for Visit 7 
(end of Week 10) in Section 8.3.2 with the addition of:
•
Brief physical examination.
•
Brief neurological examination.
For the assessment of clinical chemistry and hematology, if no abnormality is observed in the 
laboratory blood samples from the previous visit, the assessment does not have to be 
performed.
8.3.4
Visit 9 (Week 18)/Early Termination Visit 
Subjects will be asked to return to the clinic on the morning of the day prior to Visit 9 (end of 
Week 18 ±2 days)/Early Termination to begin 24-hour ambulatory EEG recordings. Scalp 
electrodes will be attached, and subjects will receive a recording device. Subjects will be 
asked to return approximately 24 hours later (for Visit 9/Early Termination Visit) for removal 
of the scalp electrodes and return of the recording device.
At Visit 9 (end of Week 18) or the Early Termination Visit (if applicable), subjects will 
return for a clinic visit, and the following will be performed:
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Complete physical examination.
•
Complete neurological examination.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 50 of 203
•
12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed prior to 
any blood draws and vital signs assessment and, if possible, with the subject in the supine 
position for approximately 5 minutes preceding the recordings and during the recordings. 
Recordings should be performed at least 15 minutes after removal of scalp electrodes 
used for the 24-hour ambulatory EEG recording).
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory subjects).
•
Body weight and height assessment.
•
Head circumference in subjects <4 years of age.
•
C-SSRS (if applicable).
•
Blood sample for clinical chemistry, hematology, and endocrinology.
•
Blood sample for LCM and concomitant AED plasma concentrations (at any time 
post-dosing with LCM). Blood sample will be drawn along with clinical chemistry and 
hematology samples.
•
Urine sample for urinalysis (if applicable).
•
Serum pregnancy test (if applicable).
•
Clinical Global Impression of Change assessment.
•
Caregiver’s Global Impression of Change assessment.
•
Achenbach CBCL (if applicable); CBCL/1½-5 or CBCL/6-18 for pediatric subjects 
≥18 months of age (same version that was used at Visit 2).
•
BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) (same version that was 
used at Visit 2).
•
PedsQL for subjects ≥1 month to ≤18 years of age (same version that was used at Visit 2).
•
Tanner Stage (if applicable). The Tanner Stage will be performed only for subjects who 
are pubescent at Visit 1 or who will enter puberty during the course of the study.
•
Subject diary return/review.
•
LCM return.
•
AE reporting.
•
Review withdrawal criteria.
•
Contact IXRS.
•
Dispense subject diary (for subjects entering Taper Period and not SP848).
•
Reminder to complete subject diary on a daily basis (if applicable).
•
Health care resource use.
•
Dispense LCM (for subjects entering Taper Period and not SP848).
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 51 of 203
Subjects may be eligible for participation in the open-label study (SP848) if they have been 
maintained on a dose of at least 4mg/kg/day (oral solution) for subjects weighing <50kg, or
200mg/day (tablets/oral solution) for subjects weighing ≥50kg in the Maintenance Period.
Subjects will begin SP848 on the LCM dose they were taking in the Maintenance Period in 
SP0966.
Subjects who choose not to participate in the open-label study or subjects who discontinue
due to other reasons will enter a 2- to 4-week Taper Period followed by a Safety Follow-Up 
Visit 2 weeks (±2 days) after the final dose of LCM and a Safety Follow-Up Telephone 
Contact 30 days (-1/+3 days) after the final dose of LCM.
Investigators should discuss treatment options with the subject and/or his/her parent/legal 
representative to best manage the subject’s epilepsy. Taper of LCM may not be required for 
some subjects who discontinue study medication prematurely, depending on the treatment 
option selected by the investigator in consultation with the subject and/or parent/legal 
representative. These subjects should complete Visit 9/Early Termination Visit and then 
complete the Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM and a
Safety Follow-Up Telephone Contact 30 days (-1/+3 days) after the final dose of LCM. The 
End of Taper Visit is not required for subjects who complete or withdraw from the study and 
who do not undergo taper of LCM.
8.4
End of Study Period
For subjects who enter the open-label study (SP848), the end of the study will be the date of 
the subject’s last assessment in SP0966 (end of Maintenance Period or Early Termination 
Visit). Subjects who do not enroll in SP848 will enter a Taper Period followed by a Safety 
Follow-Up Period as described below, and the end of the study will be the date of the last 
Safety Follow-Up Telephone Contact.
8.4.1
Taper Period
For subjects who do not enroll in the open-label study (SP848), a 2- to 4 week (depending on 
dose achieved) Taper Period will be scheduled. For subjects completing the full duration of 
the Maintenance Period, the Taper Period will begin at Week 19 (±2 days). For subjects who 
do not complete the full duration of the Maintenance Period, the Taper Period will begin 
earlier, at the time that they end the Maintenance Period. Please refer to Section 7.2 for 
details of the taper schedule. Taper of LCM may not be required for some subjects who 
discontinue study medication prematurely, depending on the treatment option selected by the 
investigator in consultation with the subject and/or parent/legal representative. These subjects 
should complete Visit 9/Early Termination Visit and then complete the Safety Follow-Up 
Visit 2 weeks (±2 days) after the final dose of LCM and a Safety Follow-Up Telephone 
Contact 30 days (-1/+3 days) after the final dose of LCM.
8.4.1.1
Telephone Contact (Week 19)
At the end of Week 19 (±2 days) during the first week of the Taper Period, the investigator or 
designee should contact the subject’s caregiver (including parent/legal representative) by 
telephone. The following assessments will be performed:
•
Concomitant AED(s) assessment
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 52 of 203
•
Concomitant medication(s) assessment
•
Reminder to complete subject diary on a daily basis
•
AE reporting
•
Review withdrawal criteria
If any AEs necessitate a subject’s withdrawal from the study, the subject should return for a 
clinic visit as soon as possible after the occurrence of the AE.
8.4.1.2
End of Taper Visit (Weeks 20 to 22)
The End of Taper Visit is not required for subjects who complete or withdraw from the study 
and who do not undergo taper of LCM. Each subject will have only 1 Taper Visit. The Taper 
Visit will be scheduled at the end of the Taper Period (Week 20, Week 21, or Week 22, 
depending on dose level achieved; see Table 7-4 and Table 7-5). A time window of ±2 days 
relative to Visit 2 (Titration Period) is applicable.
The following will be performed at the End of Taper Visit at the end of the last week of the 
Taper Period:
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Brief physical examination.
•
Brief neurological examination.
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory subjects).
•
Body weight assessment.
•
12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed prior to 
any blood draws and vital signs assessment and, if possible, with the subject in the supine 
position for approximately 5 minutes preceding the recordings and during the recordings).
•
C-SSRS (if applicable).
•
Blood sample for clinical chemistry, hematology and endocrinology.
•
Urine sample for urinalysis (if applicable).
•
Serum pregnancy test (if applicable).
•
Subject diary return/review.
•
LCM return.
•
AE reporting.
•
Review withdrawal criteria.
•
Contact IXRS.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 53 of 203
•
Health care resource use.
8.4.2
Safety Follow-up
Safety Follow-up is required only for subjects who do not enroll in the open-label study 
(SP848). 
8.4.2.1
Safety Follow-Up Visit (Weeks 22 to 24)
The Safety Follow-Up Visit will occur 2 weeks (±2 days) after the final dose of LCM. 
The following assessments will be performed:
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Complete physical examination.
•
Complete neurological examination.
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory subjects).
•
Body weight and height assessment.
•
12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed prior to 
any blood draws and vital signs assessment and, if possible, with the subject in the supine 
position for approximately 5 minutes preceding the recordings and during the recordings)
(only for subjects with an abnormal reading at the previous visit).
•
C-SSRS (if applicable).
•
Blood sample for clinical chemistry, hematology and endocrinology (only for subjects 
with an abnormal value at the previous visit). 
•
Urine sample for urinalysis (if applicable) (only for subjects with an abnormal value at 
the previous visit). 
•
Urine pregnancy test (if applicable) (only if blood is not collected for another
assessment).
•
AE reporting.
•
Health care resource use.
8.4.2.2
Safety Follow-Up Telephone Contact (Weeks 24 to 26)
The Safety Follow-Up Telephone Contact will occur 30 days (-1/+3 days) after the final dose 
of LCM and will include the following assessments:
•
Concomitant AED(s) assessment
•
Concomitant medication(s) assessment
•
AE reporting
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 54 of 203
8.5
Unscheduled Visit
Unscheduled Visits may be performed at any time after Visit 1, at the discretion of the 
investigator. During an Unscheduled Visit, the following assessments are required: 
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory subjects).
•
Body weight assessment (height is not required).
•
Subject diary return/review.
•
Reminder to complete subject diary on a daily basis.
•
AE reporting.
•
Review withdrawal criteria.
If the Unscheduled Visit is due to an AE, then the C-SSRS is required.
In addition to the required assessments listed above, the investigator can perform further 
assessments based on his/her clinical judgment and the medical needs of the subject (eg, 
assessments of ECG, laboratory tests, physical examination, neurological examination, etc).
9
ASSESSMENT OF EFFICACY
9.1
Seizure frequency
At the Screening Visit (Visit 1), seizure history will be based on the subject or caregiver 
(including parent/legal representative) being asked how many seizures the subject has had 
over the past 4 weeks.
During the study, subjects will keep a diary to record daily seizure activity from the 
Screening Visit until the end of the study. At each visit and telephone contact the subject 
and/or legal representative should be reminded to complete the subject diary on a daily basis
and to bring the diary with them to each clinic visit (including Unscheduled Visits). The 
following seizure information will be recorded in the diary:
•
Seizure type
•
Seizure frequency
The investigator should discuss the possibility of the emergence of other seizure types with 
parents and caregivers, and advise that all seizures should be recorded in the diary.
9.2
Global Impression of Change
9.2.1
Clinical Global Impression of Change
The Clinical Global Impression of Change should be completed by an investigator or 
subinvestigator. It will be used to assess the change in the subject’s clinical status that 
resulted from LCM, including an evaluation of seizure frequency and intensity, the 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 55 of 203
occurrence of AEs, and the subject’s overall functional status. The Clinical Global 
Impression of Change will be completed according to the tabular schedule of study 
procedures, Section 5.2.
9.2.2
Caregiver’s Global Impression of Change
For the assessment of the Caregiver Global Impression of Change, the caregiver (including 
parent/legal representative) should provide his/her assessment of the subject’s clinical status
that resulted from LCM, including an evaluation of seizure frequency and intensity, the 
occurrence of AEs, and subject’s overall functional status. The Caregiver Global Impression 
of Change will be completed according to the tabular schedule of study procedures, 
Section 5.2.
9.3
Pediatric Quality of Life Inventory
The PedsQL is a validated instrument that consists of generic core scales suitable for use with 
pediatric populations, including those with acute or chronic health conditions (Varni et al, 
2001; Varni et al, 2011). The PedsQL will be administered at Visit 2 and at Visit 9/Early 
Termination. For the Visit 9/Early Termination assessment, subjects will complete the 
version consistent with their age at Visit 2.
The PedsQL Measurement Model consists of developmentally appropriate forms for pediatric 
subjects ≥1 month to ≤12 months; ≥13 months to ≤24 months; >2 years to ≤4 years, ≥5 years 
to ≤7 years, ≥8 years to ≤12 years, and ≥13 years to ≤18 years of age. Self-report is measured 
for pediatric subjects ≥5 years to ≤18 years of age, and parent proxy report of child 
health-related quality of life (HRQoL) is measured for pediatric subjects ≥1 month to 
≤18 years of age. 
The multidimensional PedsQL generic core scales encompass the essential core domains for 
pediatric HRQoL measurement: Physical Functioning, Emotional Functioning, Social 
Functioning, and School Functioning. The PedsQL assessment is retrospective to the prior 
4 weeks, and individual items are scored using a 5-point Likert scale (never, almost never, 
sometimes, often, or always). A total health summary score ranging between 0 and 100 is 
calculated from the sum of the raw scores of the individual items, with higher scores 
indicating higher HRQoL.
9.4
Health care resource use
For health care resource use parameters, the following will be evaluated: concomitant AEDs, 
medical procedures, health care provider consultations not related to study, hospitalizations 
not related to study. Health care resource use parameters will be collected according to the 
tabular schedule of study procedures, Section 5.2.
10
ASSESSMENT OF PHARMACOKINETIC/ 
PHARMACODYNAMIC VARIABLES
Blood samples for the determination of LCM and concomitant AED plasma concentrations 
will be collected at Visits 2 and 9 (at any time after dosing with the exception of the sample 
at Visit 2, which should be predose) along with clinical chemistry and hematology samples 
(according to the tabular schedule of study procedures in Section 5.2). In each case, the time 
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 56 of 203
the subject took the most recent dose of LCM and concomitant AEDs and the time of blood 
sampling must be recorded. Actual sampling times will be recorded in the eCRF to the 
minute.
Details of plasma sample collection and processing, sample labeling, and shipment will be 
provided in the laboratory manual.
11
ASSESSMENT OF SAFETY
11.1
Adverse events
11.1.1
Definition of AE
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product that does not necessarily have a causal relationship 
with this treatment. An AE can therefore be any unfavorable and unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product.
In order to ensure complete safety data collection, all AEs occurring during the study 
(ie, after the signing of the ICF), including any pretreatment and posttreatment periods 
required by the protocol, must be reported in the eCRF even if no investigational product was 
taken but specific study procedures were conducted. This includes all AEs not present prior 
to the initial visit and all AEs that recurred or worsened after the initial visit.
Signs or symptoms of the condition/disease for which the investigational product is being 
studied should be recorded as AEs only if their nature changes considerably or their 
frequency or intensity increases in a clinically significant manner as compared to the clinical 
profile known to the investigator from the subject’s history or the Baseline Period.
11.1.2
Procedures for reporting and recording AEs
The subject will be given the opportunity to report AEs spontaneously. A general prompt will 
also be given at each study visit to detect AEs. For example:
“Did you notice anything unusual about your health (since your last visit)?”
In addition, the investigator should review any self-assessment procedures (eg, diary cards) 
employed in the study.
11.1.3
Description of AEs
When recording an AE, the investigator should use the overall diagnosis or syndrome using 
standard medical terminology, rather than recording individual symptoms or signs. The eCRF 
and source documents should be consistent. Any discrepancies between the subject’s own 
words on his/her own records (eg, diary card) and the corresponding medical terminology
should be clarified in the source documentation.
Details for completion of the AE eCRF (including judgment of relationship to LCM) are 
described in the eCRF Completion Guidelines.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 57 of 203
11.1.4
Follow up of AEs
An AE should be followed until it has resolved, has a stable sequelae, the investigator 
determines that it is no longer clinically significant, or the subject is lost to follow up. 
If an AE is ongoing at the end of the study for a subject, follow up should be provided until 
resolution/stable level of sequelae is achieved, or until the investigator no longer deems that it 
is clinically significant, or until the subject is lost to follow up. If no follow up is provided, 
the investigator must provide a justification. The follow up will usually be continued for 30
days after the subject has discontinued his/her IMP.
11.1.5
Rule for repetition of an AE
An increase in the intensity of an AE should lead to the repetition of the AE being reported 
with:
•
The outcome date of the first AE that is not related to the natural course of the disease 
being the same as the start date of the repeated AE, and the outcome of “worsening”
•
The AE verbatim term being the same for the first and repeated AE, so that the repeated 
AE can be easily identified as the worsening of the first one
11.1.6
Pregnancy
Should a subject become pregnant after the first intake of any IMP, the UCB Drug Safety
department should be informed immediately. The subject should be withdrawn from the 
study as soon as pregnancy is known, and the following should be completed:
•
The subject should return for the Early Termination Visit.
•
The subject should immediately stop the intake of the IMP or be down-titrated as 
instructed at the Early Termination Visit. 
•
A Safety Follow-Up Visit should occur 2 weeks ±2 days after the subject has 
discontinued IMP.
•
A Safety Follow-Up Telephone Contact should occur 30 days (-1/+3 days) after the 
subject has discontinued IMP.
The investigator must inform the subject of information currently known about potential risks 
and about available treatment alternatives.
In cases where the partner of a male subject enrolled in a clinical study becomes pregnant, 
UCB will ask the investigator or designee to contact the subject and his partner to request 
consent via the Partner Pregnancy Consent form. If the partner agrees to provide additional 
information, the Pregnancy Report and Outcome form will be forwarded to the subject’s 
partner for completion.
The pregnancy will be documented on the Pregnancy Report and Outcome form provided to 
the investigator. The progression of the pregnancy and the eventual birth (if applicable) must 
be followed-up using the Pregnancy Report and Outcome form in which the investigator has 
to report on the health of the mother and of the child. The health of the child must be 
followed for 30 days after birth for any significant medical issues.
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 58 of 203
In certain circumstances, UCB may request that follow up is continued for a period longer 
than 30 days.
A pregnancy becomes a serious adverse event (SAE) in the following circumstances: 
miscarriage, abortion, or anomaly/birth defect of the child. Those SAEs must be additionally 
reported using the Investigator SAE Report form.
11.1.7
Overdose of IMP
Excessive dosing (beyond that prescribed in the protocol and including overdose) should be 
recorded in the Drug Accountability or Study Drug Dosing module of the eCRF. Any SAE or 
nonserious AE associated with excessive dosing must be followed as any other SAE or 
nonserious AE. These events may be symptomatic, in that the excessive dosing results in 
clinical signs and symptoms, or the excessive intake may itself be an AE. 
11.1.8
Safety signal detection
Selected data from this study will be reviewed periodically to detect as early as possible any 
safety concern(s) related to the IMP so that investigators, clinical study subjects, regulatory 
authorities, and IRBs/IECs will be informed appropriately and as early as possible.
The Study Physician or medically qualified designee/equivalent will conduct an ongoing 
review of SAEs and perform ongoing SAE reconciliations in collaboration with the Drug 
Safety representative.
As appropriate for the stage of development and accumulated experience with the IMP, 
medically qualified personnel at UCB may identify additional safety measures (eg, AEs, vital 
signs, laboratory or ECG results) for which data will be periodically reviewed during the 
course of the study.
A DMC will oversee the safety of the study. See Section 13.7 for further details.
11.2
Serious adverse events
11.2.1
Definition of SAE
Once it is determined that a subject experienced an AE, the seriousness of the AE must be 
determined. An SAE must meet 1 or more of the following criteria:
•
Death
•
Life-threatening
(Life-threatening does not include a reaction that might have caused death had it occurred
in a more severe form.)
•
Significant or persistent disability/incapacity
•
Congenital anomaly/birth defect (including that occurring in a fetus)
•
Important medical event that, based upon appropriate medical judgment, may jeopardize 
the patient or subject and may require medical or surgical intervention to prevent 1 of the 
other outcomes listed in the definition of serious
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 59 of 203
(Important medical events may include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, blood dyscrasias that do not result in 
inpatient hospitalization, or the development of drug dependency or drug abuse.)
•
Initial inpatient hospitalization or prolongation of hospitalization
(A patient admitted to a hospital, even if he/she is released on the same day, meets the 
criteria for the initial inpatient hospitalization. An emergency room visit that results in 
admission to the hospital would also qualify for the initial inpatient hospitalization 
criteria. However, emergency room visits that do not result in admission to the hospital 
would not qualify for this criteria and, instead, should be evaluated for 1 of the other 
criteria in the definition of serious [eg, life-threatening adverse experience, important 
medical event].
Hospitalizations for reasons not associated with the occurrence of an AE [eg, preplanned 
surgery or elective surgery for a pre-existing condition that has not worsened or 
manifested in an unusual or uncharacteristic manner] do not qualify for reporting. For 
example, if a subject has a condition recorded on his/her medical history and later has a 
preplanned surgery for this condition, it is not appropriate to record the surgery or 
hospitalization as an SAE, since there is no AE upon which to assess the serious criteria. 
Please note that, if the pre-existing condition has worsened or manifested in an unusual or 
uncharacteristic manner, this would then qualify as an AE and, if necessary, the 
seriousness of the event would need to be determined.)
Hospitalization for the 24-hour ambulatory EEG assessments planned in this protocol will 
not be considered SAEs.
11.2.2
Procedures for reporting SAEs
If an SAE is reported, UCB must be informed within 24 hours of receipt of this information 
by the site (see contact information for SAE reporting listed in the SAE Reporting section at 
the front of the protocol). The investigator must forward to UCB (or its representative) a duly 
completed “Investigator SAE Report Form for Development Drug” (SAE report form) 
provided by UCB, even if the data are incomplete, or if it is obvious that more data will be 
needed in order to draw any conclusions. Information recorded on this form will be entered 
into the global safety database.
An Investigator SAE Report form will be provided to the investigator. The Investigator SAE 
Report form must be completed in English. 
It is important for the investigator, when completing the SAE report form, to include the 
assessment as to a causal relationship between the SAE and the IMP administration. This 
insight from the investigator is very important for UCB to consider in assessing the safety of 
the IMP and in determining whether the SAE requires reporting to the regulatory authorities 
in an expedited manner.
Additional information (eg, autopsy or laboratory reports) received by the investigator must 
be provided within 24 hours. All documents in the local language must be accompanied by a 
translation in English, or the relevant information included in the same document must be 
summarized in the Investigator SAE report form.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 60 of 203
The investigator is specifically requested to collect and report to UCB (or its representative) 
any SAEs (even if the investigator is certain that they are in no way associated with the IMP), 
up to 30 days from the end of the study for each subject, and to also inform participating 
subjects of the need to inform the investigator of any SAE within this period. Serious AEs 
that the investigator thinks may be associated with the IMP must be reported to UCB 
regardless of the time between the event and the end of the study.
Upon receipt of the SAE report form, UCB will perform an assessment of expectedness of the 
reported SAE. The assessment of the expectedness of the SAE is based on the Investigator’s 
Brochure.
11.2.3
Follow up of SAEs
An SAE should be followed until it has resolved, has a stable sequelae, the investigator 
determines that it is no longer clinically significant, or the subject is lost to follow up. 
Information on SAEs obtained after clinical database lock will be captured through the Drug 
Safety database without limitation of time.
11.3
Adverse events of special interest
An AE of special interest is any AE that a regulatory authority has mandated be reported on 
an expedited basis, regardless of the seriousness, expectedness, or relatedness of the AE to 
the administration of a UCB product/compound.
The following are LCM 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 for 
subject’s age
•
Syncope or loss of consciousness (other than seizure-related)
•
Serious suspected multiorgan hypersensitivity reactions
Serious suspected multiorgan hypersensitivity cases may be identified and reported to the 
sponsor by the investigator using the following algorithm as agreed with the USA Food 
and Drug Administration (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%
◦
Eosinophils absolute ≥0.5G/L
◦
Neutrophils absolute <1.5G/L
◦
Platelets ≤100G/L
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 61 of 203
◦
ALT ≥2x ULN
◦
AST ≥2x ULN
Adverse events of special interest must be reported in the same way as SAEs 
(see Section 11.2.2).
11.4
Immediate reporting of AEs
The following AEs must be reported immediately by the investigator to the sponsor:
•
SAE: AE that the investigator classifies as serious by the above definitions regardless of 
causality.
•
Suspected transmission of an infectious agent via a medicinal product.
•
AE of special interest (see Section 11.3).
11.5
Anticipated SAEs
The following list of Anticipated SAEs has been identified, as these events are anticipated to 
occur in the epilepsy population studied in this protocol at some frequency that is 
independent of drug exposure. This original list will remain in effect for the duration of the 
protocol.
This list does not change the investigator’s obligation to report all SAEs (including 
Anticipated SAEs) as detailed in Section 11.2.2.
Table 11‒1
Anticipated SAEs for the pediatric epilepsy population
MedDRA system organ class
MedDRA preferred term
Congenital, familial, and genetic disorders 
Teratogenicity
General disorders and administration site 
disorders
Sudden unexplained death in epilepsy
Nervous system disorders
Convulsion
Incontinence
Status epilepticus
Pregnancy, puerperium, and perinatal disorders
Abortion spontaneous
Psychiatric disorders
Psychotic behavior
Abnormal behavior
Anxiety
Sleep disorder
Reproductive system and breast disorders
Menstrual disorder
MedDRA=Medical Dictionary for Regulatory Activities
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 62 of 203
11.6
Laboratory measurements
Blood and urine specimens for routine assay of hematology, clinical chemistry, and urinalysis 
testing will be collected according to the tabular schedule of study procedures, Section 5.2. 
Urinalysis will be performed for subjects aged 5 to 17 years only. A central laboratory will 
perform the routine analysis of blood and urine specimens. Pregnancy testing will also be 
performed (see Section 11.6.3). The procedures for handling and shipping these specimens
will be provided to the sites.
The laboratory tests to be performed are presented in Table 11‒2.
Table 11‒2
Laboratory measurements
Hematology
Chemistry
Urinalysis
RBC count
WBC count
Differential count
Platelet count
Hematocrit
Hemoglobin
Calcium
Serum electrolytes (sodium, 
potassium, chloride, 
bicarbonate)
Total serum protein
Albumin
Phosphorus
Glucose
Uric acid
Alkaline phosphatase
BUN
Creatinine
AST
ALT
GGT
Total bilirubin
Cholesterol
Triglycerides
Albumin
Specific gravity
Ketones
Glucose
pH
Microscopic exam for blood cells or 
casts/high power field
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
GGT=gamma-glutamyltransferase; RBC=red blood cell; WBC=white blood cell
11.6.1
Additional laboratory tests
In order to assess changes in thyroid and sex hormone concentrations, laboratory tests for 
FSH, LH, T3, T4, TSH, and testosterone, as appropriate, will be performed. The assessments 
will be performed according to the tabular schedule of study procedures (Section 5.2). The
use of any oral contraceptives should be recorded. 
11.6.2
Liver function tests
Refer to Section 6.3 for LFT withdrawal criteria. 
Transaminases (AST, ALT, or both) ≥3xULN but <5xULN, in the presence of total bilirubin 
≥2xULN, or transaminases (AST, ALT, or both) ≥5xULN will result in immediate 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 63 of 203
discontinuation of LCM and withdrawal of the subject from the study. The LFTs will be 
repeated as soon as possible, and in no case >1 week later.
Transaminases (AST, ALT, or both) ≥3xULN to <5xULN, in the presence of normal total 
bilirubin, will be repeated within a few days. If the repeat testing confirms the abnormality 
(ie, transaminases are ≥3xULN to <5xULN with normal bilirubin), then weekly monitoring 
of LFTs should continue until resolved (ie, <3xULN or stable condition). The investigator is 
to decide whether or not to stop the study medication. 
In all cases of transaminases (AST, ALT, or both) ≥3xULN, testing for hepatitis A, B, and C 
will be done.
Referral to a specialist (ie, hepatologist or gastroenterologist) is at the discretion of the 
investigator. This is recommended especially if the transaminase abnormalities >3xULN 
persist after discontinuation of the study medication.
11.6.3
Pregnancy testing
Females of childbearing potential will have serum and urine pregnancy tests performed 
during the study according to the tabular schedule of study procedures; see Section 5.2.
11.7
Other safety measurements
11.7.1
Seizure frequency
See Section 9.1.
11.7.2
24-hour ambulatory EEG
Subjects will be asked to return to the clinic on the morning of the day prior to Visit 2, 
Visit 6, and Visit 9/Early Termination to begin 24-hour ambulatory EEG recordings for 
evaluation of spike-wave discharges.
11.7.3
12-lead ECG
Standard 12-lead ECGs will be performed according to the tabular schedule of study 
procedures in Section 5.2. Two interpretable recordings approximately 20 to 30 minutes apart
are required. At Visit 2, Visit 6, and Visit 9/Early Termination, the 12-lead ECG recordings
should be performed at least 15 minutes after removal of scalp electrodes used for the 
24-hour ambulatory EEG recording and prior to blood sample collection. At all other visits, 
2 recordings will be performed prior to blood sample collection and measurement of vital 
signs.
Care should be taken to assure proper lead placement and quality ECG recordings. Subjects 
should rest in the supine position for approximately 5 minutes before the ECG recordings and 
during the recordings, if possible.
11.7.3.1
Overall ECG interpretation
An immediate initial review of the ECGs will be conducted locally by the investigator, 
subinvestigator, or qualified designated reader. If this reading identifies abnormal ECG 
findings that are assessed by the investigator or subinvestigator to be clinically significant, 
then the ECG should be repeated in 1 hour, unless circumstances require a more rapid 
assessment. If the clinically significant abnormality is confirmed by the repeat ECG or if the 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 64 of 203
investigator feels it is medically necessary, then the subject must be withdrawn from the 
study (see Section 6.3). The investigator may consult with the cardiologist at the central ECG 
laboratory to confirm the presence of a clinically significant ECG abnormality. It remains the 
responsibility of the investigator to decide whether an ECG finding is of clinical significance 
on the basis of the complete clinical picture and whether this finding influences the subject’s 
participation in the study.
11.7.4
Vital signs, body weight and height
Noninvasive BP (systolic and diastolic) and pulse rate will be measured at clinic visits after at 
least 3 minutes at rest in a supine position, according to the tabular schedule of study 
procedures (Section 5.2). Assessment of orthostatic changes (only in ambulatory subjects) 
will be as follows: after the 3-minute measurement in supine position, the subject is asked to 
stand up, and BP and pulse rate are taken at approximately 1 minute and 3 minutes after 
standing up, as feasible. Body weight will be determined without shoes and wearing light 
clothing, and height will be measured without shoes. Body weight and height will be assessed 
according to the tabular schedule of study procedures in Section 5.2.
11.7.5
Physical examination 
The physical examination should be performed by a medically qualified clinician licensed to 
perform the examination, according to the tabular schedule of study procedures in 
Section 5.2. If possible, the same clinician should conduct all physical examinations for the 
same subject during the study. Subsequent to Visit 1, clinically significant physical 
examination findings should be reported as AEs.
11.7.5.1
Complete physical examination
The complete physical examination will include cardiac and respiratory function via 
auscultation, temperature, and review of all body systems. Genitourinary and breast 
examinations will not be performed. 
11.7.5.2
Brief physical examination 
The brief physical examination will include review of the following body systems:
•
Cardiovascular
•
Pulmonary
•
Abdominal (hepato-gastrointestinal)
•
Dermatologic
11.7.6
Neurological examination 
Neurological examinations will be performed by a medically qualified clinician with 
documented training in the conduct of neurological examinations, according to the tabular 
schedule of study procedures in Section 5.2. If possible, the same clinician should conduct all 
neurological examinations for the same subject during the study. The investigator or 
subinvestigator is responsible for confirming the diagnosis of generalized seizures.
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 65 of 203
11.7.6.1
Complete neurological examination 
The complete neurological examination will include selected assessment of mental status, 
sensory systems, motor functions, cranial nerves, reflexes, level of consciousness, speech, 
and coordination/cerebellar function.
11.7.6.2
Brief neurological examination
The brief neurological examination will include selected assessment of mental status, level of 
consciousness, reflexes, muscle strength, and coordination/cerebellar function.
11.7.7
Tanner Stage
At Visit 1 and Visit 9 (or the Early Termination Visit) for applicable subjects, the investigator
or qualified designee will evaluate the subject’s sexual development using the 3-item scale. 
The investigator should use clinical judgment in deciding which subjects are selected for 
evaluation of Tanner Stage (ie, those subjects who are pubescent at Visit 1 or those subjects 
who become pubescent during the course of the study).
11.7.8
Achenbach CBCL
The Achenbach CBCL is a widely used validated questionnaire to evaluate a child’s 
competencies and behavioral/emotional problems. Behavioral problems will be scored by the 
parent(s) or legal representative(s). Depending on the subject’s age, 1 of 2 versions of the 
CBCL will be used. The CBCL/1½-5 checklist is intended for use in pediatric subjects aged 
between 18 months and 5 years and 11 months. For subjects between 6 and <18 years, the 
CBCL/6-18 version will be used. The Achenbach CBCL will not be applied to pediatric 
subjects <18 months of age. 
The same scale will be completed at Visit 2, Visit 6, and Visit 9 (or the Early Termination 
Visit) and again by the same parent(s) or legal representative(s) in the open-label study, 
SP848 (if applicable). The completion of the Achenbach CBCL will require approximately 
45 minutes. 
In both questionnaires, the occurrence of certain problems and behaviors in the past 6 months 
will be scored on the following scale: 
•
0=not true (as far as known)
•
1=somewhat or sometimes true
•
2=very true or often true
Eight syndrome scores will be calculated from these questions, which will in turn be 
summarized by 2 composite scores. Additionally, for each score on the question, syndrome, 
and total level, categorizations based on a normative sample will be used to evaluate normal, 
borderline, or clinically relevant behavior. 
In addition, the Achenbach CBCL/6-18 includes ratings related to performance in school, 
activities in leisure time, and special interests. 
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 66 of 203
11.7.9
Bayley Scales of Infant and Toddler Development, Third Edition
The Bayley-III scales are recognized internationally as one of the most comprehensive 
developmental assessment instruments (Sattler and Hoge, 2006) used to examine the major 
facets of a young child’s development (Bayley, 2006). The Bayley-III scales are a 
standardized, individually administered adaptive assessment that measures the developmental 
functioning of infants and young pediatric subjects from 1 month to 42 months of age 
(Bayley, 2006). The Bayley-III scales measure cognitive, language, motor, social-emotional, 
and adaptive development and are a revision of the predecessor, the Bayley Scales of Infant 
Development, Second Edition (Bayley, 1993). The Bayley-III scales are a technically sound 
instrument, with strong internal consistency, as well as test-retest stability. The Bayley-III 
scales are validated only in English. 
This scale is validated as a tool for assessment of neurological development in young 
pediatric subjects and is therefore considered appropriate for SP0966. 
The Bayley-III scales are an individually administered adaptive assessment that presents 
pediatric subjects with situations and tasks designed to produce an observable set of 
behavioral responses. They consist of a cognitive scale, a language composite scale with 
receptive and expressive language subscales, and a motor composite scale with fine and gross 
motor subscales to be completed by the investigator or designee. It also has a 
social-emotional scale, comprising social-emotional competence, and sensory processing, and 
an adaptive behavior scale, which assesses the attainment of skills necessary for the 
development of independence, to be completed by the child’s parent or caregiver. 
The completion of the Bayley-III scales will require approximately 50 minutes for pediatric
subjects who are 12 months old or younger and 90 minutes for pediatric subjects aged 
12 months to 18 months. 
The same scale will be completed at Visit 2 and again in the open-label study, SP848 (if 
applicable).
11.7.10
Behavior Rating Inventory of Executive Function
The BRIEF-P and the BRIEF are validated tools that will be used for the evaluation of 
subjects ≥2 years to <5 years of age and ≥5 years of age, respectively. The BRIEF-P/BRIEF 
will be administered at Visit 2 and at Visit 9/Early Termination. For the Visit 9/Early 
Termination assessment, subjects will complete the version consistent with their age at 
Visit 2.
The BRIEF-P and BRIEF include rating forms used by parents to assess subjects’ executive 
functioning. Executive functions broadly encompass a set of cognitive skills that are 
responsible for the planning, initiation, sequencing, and monitoring of complex goal-directed 
behavior.
The BRIEF-P rating form consists of items that measure various aspects of executive 
functioning: Inhibit, Shift, Emotional Control, Working Memory, and Plan/Organize. The 
clinical scales form 3 broad indexes (Inhibitory Self-Control, Flexibility, and Emergent 
Metacognition) and 1 composite score (Global Executive Composite).
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 67 of 203
The BRIEF rating form contains items in nonoverlapping clinical scales. These theoretically 
and statistically derived scales form 2 broader Indexes: Behavioral Regulation (3 scales) and 
Metacognition (5 scales), as well as a Global Executive Composite score.
Both the BRIEF-P and the BRIEF include validity scales to measure negativity and 
inconsistency of responses.
11.7.11
Assessment of suicidality
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia 
University Medical Center, 2008). For subjects ≥6 years of age, this scale will be used for 
screening as well as to assess suicidal ideation and behavior that may occur during the study. 
The C-SSRS will be completed according to the tabular schedule of study procedures in 
Section 5.2.
The “Since Last Visit” version of the C-SSRS will be used, with the following exceptions:
•
The “Baseline/Screening” version of the C-SSRS should be completed at Visit 1.
•
If a subject turns 6 years of age during the study, the “Already Enrolled” version of the
C-SSRS should be completed at the first visit after the sixth birthday.
The C-SSRS is not validated for subjects <6 years of age and will not be used for this 
population. Subjects should be monitored for any changes in mood, ideas, or behavior for 
warning signs of depression. The investigator should be aware of common warning signs that 
might be a signal for risk of depression. For common signs and symptoms of depression in 
children younger than 6 years old, reference should be made to the current version of the 
Diagnostic and Statistical Manual of Mental Disorders. Parents and caregivers should also be 
advised accordingly and effort should be made at clinic visits to specifically assess potential 
depression.
12
STUDY MANAGEMENT AND ADMINISTRATION 
12.1
Adherence to protocol
The investigator should not deviate from the protocol. However, the investigator should take 
any measure necessary in deviation from or not defined by the protocol in order to protect 
clinical study subjects from any immediate hazard to their health and safety. In this case, this 
action should be taken immediately, without prior notification of the regulatory authority, 
IRB/IEC, or sponsor. 
After implementation of such measure, the investigator must notify the Clinical Project 
Manager of the sponsor within 24 hours and follow any local regulatory requirements.
12.2
Monitoring
UCB (or designee) will monitor the study to meet the sponsor’s monitoring Standard 
Operating Procedures (SOPs), ICH-GCP guideline, and applicable regulatory requirements, 
and to ensure that study initiation, conduct, and closure are adequate. Monitoring of the study 
may be delegated by UCB to a contract research organization (CRO) or a contract monitor.
The investigator and his/her staff are expected to cooperate with UCB (or designee) and to be 
available during the monitoring visits to answer questions sufficiently and to provide any 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 68 of 203
missing information. The investigator(s)/institution(s) will permit direct access to source 
data/documents for study-related monitoring, audits, IRB/IEC review, and regulatory 
inspection(s).
The investigator will allow UCB (or designee) to periodically review all eCRFs and 
corresponding source documents (eg, hospital and laboratory records for each study 
participant). Monitoring visits will provide UCB (or designee) with the opportunity to 
evaluate the progress of the study, verify the accuracy and completeness of eCRFs, ensure 
that all protocol requirements, applicable authorities regulations, and investigator’s 
obligations are being fulfilled, and resolve any inconsistencies in the study records.
12.2.1
Definition of source data 
All source documents must be accurate, clear, unambiguous, permanent, and capable of being 
audited. They should be made using some permanent form of recording (ink, typing, printing, 
optical disc). They should not be obscured by correction fluid or have temporary attachments 
(such as removable self-stick notes). 
Source documents are original records in which raw data are first recorded. These may 
include hospital/clinic/general practitioner records, charts, diaries, x-rays, laboratory results, 
printouts, pharmacy records, care records, ECG or other printouts, completed scales, or 
quality of life questionnaires, for example. Source documents should be kept in a secure, 
limited access area.
Source documents that are computer generated and stored electronically must be printed for 
review by the monitor (eg, ECG reports). Once printed, these copies should be signed and 
dated by the investigator and become a permanent part of the subject’s source documents. 
The 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. If the 
monitor is given access to the electronic data, the computer-generated documents do not need 
to be printed.
Electronic data records, such as Holter monitor records or EEG records, must be saved and 
stored as instructed by UCB (or designee).
12.2.2
Source data verification
Source data verification ensures accuracy and credibility of the data obtained. During 
monitoring visits, reported data are reviewed with regard to being accurate, complete, and 
verifiable from source documents (eg, subject files, recordings from automated instruments, 
tracings [ECG], x-ray films, laboratory notes). All data reported on the eCRF should be 
supported by source documents, unless otherwise specified in Section 12.2.1.
12.3
Data handling
12.3.1
Case Report form completion
The study will be performed using remote data capture; the investigator is responsible for 
prompt reporting of accurate, complete, and legible data in the eCRFs and in all required 
reports.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 69 of 203
Any change or correction to the eCRF after saving must be accompanied by a reason for the 
change.
Corrections made after the investigator’s review and approval (by means of a 
password/electronic signature) will be reapproved by the investigator.
The investigator should maintain a list of personnel authorized to enter data into the eCRF.
Detailed instructions will be provided in the eCRF Completion Guidelines.
12.3.2
Database entry and reconciliation
Case Report forms/external electronic data will be entered/loaded into a validated electronic 
database using a clinical data management system (CDMS). Computerized data cleaning 
checks will be used in addition to manual review to check for discrepancies and to ensure 
consistency of the data. The data are entered into the eCRFs once and are subsequently 
verified.
An electronic audit trail system will be maintained within the CDMS to track all data changes 
in the database once the data have been saved initially into the system or electronically 
loaded. Regular backups of the electronic data will be performed.
12.3.3
Subject Screening and Enrollment log/Subject Identification Code 
list
The subject’s screening and enrollment will be recorded in the Subject Screening and 
Enrollment Log.
The investigator will keep a Subject Identification Code list. This list remains with the 
investigator and is used for unambiguous identification of each subject.
The subject’s consent and enrollment in the study must be recorded in the subject’s medical 
record. These data should identify the study and document the dates of the subject’s 
participation.
12.4
Termination of the study
UCB reserves the right to temporarily suspend or prematurely discontinue this study either at 
a single site, multiple sites, or at all sites at any time for reasons including, but not limited to, 
safety or ethical issues, inaccurate or incomplete data recording, noncompliance, or 
unsatisfactory enrollment with respect to quality or quantity.
If the study is prematurely terminated or suspended, UCB (or its representative) will inform 
the investigators/institutions and the regulatory authority(ies) of the termination or suspension 
and the reason(s) for the termination or suspension, in accordance with applicable regulatory 
requirement(s). The IRB/IEC should also be informed and provided with reason(s) for the 
termination or suspension by the sponsor or by the investigator/institution, as specified by the 
applicable regulatory requirement(s). In addition, arrangements will be made for the return of 
all unused LCM and other material in accordance with UCB procedures for the study.
12.5
Archiving and data retention
The investigator will maintain adequate records for the study, including eCRFs, medical 
records, laboratory results, Informed Consent documents, drug dispensing and disposition 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
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Page 70 of 203
records, safety reports, information regarding participants who discontinued, and other 
pertinent data.
All essential documents are to be retained by the investigator until at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years have elapsed since 
the formal discontinuation of clinical development of the investigational product. These 
documents should be retained for a longer period, however, if required by the applicable 
regulatory requirement(s) or by an agreement with UCB (Committee for Proprietary 
Medicinal Products [CPMP]/ICH/135/95, 2002 [Section 4.9.5]). The investigator will contact 
UCB for authorization prior to the destruction of any study records or in the event of 
accidental loss or destruction of any study records. The investigator will also notify UCB 
should he/she relocate or move the study-related files to a location other than that specified in 
the sponsor’s study master file.
12.6
Audit and inspection
The investigator will permit study-related audits mandated by UCB, after reasonable notice, 
and inspections by domestic or foreign regulatory authorities.
The main purposes of an audit or inspection are to confirm that the rights and well-being of 
the subjects enrolled have been protected, that enrolled subjects (ie, signing consent and 
undergoing study procedures) are appropriate for the study, and that all data relevant for the 
evaluation of the IMP have been processed and reported in compliance with the planned 
arrangements, the protocol, investigational site, and IRB/IEC SOPs, ICH-GCP, and 
applicable regulatory requirements.
The investigator will provide direct access to all study documents, source records, and source 
data. If an inspection by a regulatory authority is announced, the investigator will 
immediately inform UCB (or designee).
12.7
Good Clinical Practice
Noncompliance with the protocol, ICH-GCP, or local regulatory requirements by the 
investigator, institution, institution staff, or designees of the sponsor will lead to prompt 
action by UCB to secure compliance. Continued noncompliance may result in the termination 
of the site’s involvement in the study.
13
STATISTICS
A description of statistical methods follows and will be described in more detail in the 
Statistical Analysis Plan.
13.1
Definition of analysis sets
The primary analysis set will be the Safety Set (SS) and will include all enrolled subjects who 
take at least 1 dose of LCM.
The analysis set for the preliminary efficacy variables will be the Full Analysis Set and will 
include all subjects in the SS having had a Baseline and at least 1 post-Baseline efficacy 
related assessment.
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 71 of 203
13.2
General statistical considerations
In general, descriptive statistics will be used to provide an overview of the primary, 
secondary, and other variable results. For categorical parameters, the number and percentage 
of subjects in each category will be presented. The denominator for percentages will be based 
on the number of subjects appropriate for the purpose of analysis. For continuous parameters, 
descriptive statistics will include number of subjects, mean, standard deviation, median, 
minimum, and maximum.
Unless otherwise specified, Baseline will be based on the last nonmissing data collected prior 
to the first dose of LCM, ie, assessments on Visit 1 or Visit 2. Baseline of seizure data will be 
defined as the data collected in the seizure diary during the Baseline Period, ie, from Visit 1 
up to 1 day prior to Visit 2.
13.3
Planned safety analyses
13.3.1
Analysis of the primary safety variables
The actual change in the count of generalized spike-wave discharges on 24-hour ambulatory 
EEG from Visit 2 to Visit 6 will be calculated and summarized descriptively.
The change in the number of days with any generalized seizure from the Baseline Period to 
the Maintenance Period (absence, myoclonic, clonic, tonic, tonic-clonic, atonic, and partial 
evolving to secondarily generalized) will be calculated and summarized descriptively. For 
these analyses the number of days with seizures will be normalized to days per 28 days. The 
assessment of seizure days will be based on the seizure diary.
13.3.2
Secondary safety variables
The actual change in the count of 3Hz spike-wave discharges on 24-hour ambulatory EEG 
from Visit 2 to Visit 6 will be calculated and summarized descriptively.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®). Summary tables for number and percentage of subjects reporting at least 
1 TEAE tabulated by System Organ Class and preferred term will be presented. Furthermore, 
TEAEs that lead to early discontinuation from the study and serious TEAEs will be tabulated. 
Treatment-emergent AEs will be defined as those events which start on or after the date of 
first LCM administration and within 30 days following the date of last LCM administration, 
or whose severity worsens within this time frame.
Subject withdrawal due to AEs will be analyzed by presenting number and percentage of 
subjects with "AE(s)" given as primary reason of premature study discontinuation.
13.3.3
Other safety analyses
Other variables assessing safety are: ECG, measurements of laboratory parameters 
(hematology, clinical chemistry, urinalysis, and hormone status) and vital signs (including 
body weight, height and BMI), physical and neurological examination findings, assessments 
of Tanner stage (if applicable), Achenbach CBCL, and BRIEF-P/BRIEF.
Measurement and change from Baseline in continuous parameters (eg, vital signs and 
laboratory measurements) will be summarized using descriptive statistics. When analyzing 
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 72 of 203
categorical data (eg, overall assessment of 12-lead ECG) the number and percentage of 
subjects in each category will be presented. In addition, shift tables may be used to evaluate 
the number and percentage of subjects having a different post-Baseline status when compared 
to their Baseline status.
The analysis of the Bayley-III scales data will be performed in the follow-up study, SP848.
13.4
Planned preliminary efficacy and other analyses
13.4.1
Preliminary efficacy analyses
Percent change in seizure days is calculated as the respective seizure days per 28 days during 
the Maintenance Period minus respective seizure days during Baseline per 28 days divided by 
Baseline days and then multiplied by 100. The respective seizure days per 28 days will be 
calculated as ([number of seizure days over the specified time interval] divided by [number of 
days in the interval]) multiplied by 28. Seizure days for all generalized seizure types will be 
based on the seizure diary.
Descriptive statistics to summarize the absolute and percent change in seizure days per 
28 days from Baseline Period to the Maintenance Period will be presented for any 
generalized seizures reported and for each generalized seizure type.
The actual change in the count of generalized and 3Hz spike-wave discharges on 24-hour 
ambulatory EEG from Visit 2 to Visit 9 or Early Termination will be calculated and 
summarized descriptively.
Descriptive summaries will also be presented for the Clinical and Caregiver’s Global 
Impression of Change, health care resource use, and the PedsQL.
13.4.2
Pharmacokinetic analyses
A listing of LCM and AED plasma concentrations will be presented. A statistical analysis of 
the effect of LCM on AED concentrations will be performed.
13.5
Handling of protocol deviations
Important protocol deviations are deviations from the protocol which potentially could have a 
meaningful impact on either primary efficacy outcome or key safety outcomes for an 
individual subject. The criteria for identifying important protocol deviations and the 
classification of important protocol deviations will be defined within the project Data 
Cleaning Plan. To the extent feasible, rules for identifying protocol deviations will be defined 
without review of the data and without consideration of the frequency of occurrence of such 
deviations. Whenever possible, criteria for identifying important protocol deviations will be 
implemented algorithmically to ensure consistency in the classification of important protocol 
deviations across all subjects.
Important protocol deviations will be reviewed as part of the blinded data cleaning meetings 
prior to database lock to confirm exclusion from analysis sets.
13.6
Handling of dropouts or missing data
Subjects who prematurely discontinue the study will be evaluated based on the data collected 
at each visit attended.
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
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To assess the change and percent change in seizure days for generalized seizure types 
(absence, myoclonic, clonic, tonic, tonic-clonic, atonic, and partial evolving to secondarily 
generalized) and any generalized seizures from the Baseline Period to the Maintenance 
Period for subjects who prematurely discontinue the study, a last observation carried forward 
convention will be applied in the following manner to obtain an estimate for the Maintenance 
Period:
•
Subjects discontinued prematurely during the Titration Period: estimates will be 
calculated using all available data in the Titration Period and carried forward for the 
Maintenance Period.
•
Subjects discontinued prematurely during the Maintenance Period: estimates will be 
calculated using all available data in the Maintenance Period and carried forward for the 
entire Maintenance Period. 
•
Subjects completing the Maintenance Period: estimates will be calculated using all data 
from the Maintenance Period.
The imputation for data will not be carried forward into the End-of-Study Period.
No further substitution of missing data will be conducted.
13.7
Planned interim analysis and data monitoring
No formal interim analysis is planned for this study; however, data will be presented to and 
reviewed by a DMC. The DMC will oversee the safety of the study by convening to review 
safety data after 15 subjects have completed Visit 6 or withdrawn from the study, then again 
after 30 subjects have completed Visit 6 or withdrawn from the study. The DMC will consist 
of a UCB neurologist, a neurologist from the European region, a drug safety physician, a 
biostatistician, and an independent medical expert. Study enrollment will not be halted during 
planned DMC review of the safety data. The 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.
13.8
Determination of sample size
A total of 50 evaluable subjects are planned for enrollment for this study across 2 age groups. 
The first age group will consist of approximately 40 subjects between 4 years and <18 years 
of age. The second age group will consist of at least 10 subjects between 1 month and 
<4 years of age. Since the primary objective of this open-label exploratory study is to assess 
the safety and preliminary efficacy of LCM in subjects with generalized seizures and other
epilepsy syndromes, a sample size of 50 evaluable subjects is deemed adequate for meeting 
the objectives of the study. No formal sample size calculations were performed.
14
ETHICS AND REGULATORY REQUIREMENTS
14.1
Informed consent
Informed consent must be obtained from the subject’s parent/legal representative and 
documented in accordance with local regulations, ICH-GCP requirements, and the ethical 
principles that have their origin in the principles of the Declaration of Helsinki. When 
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Clinical Study Protocol
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possible or as required according to local IRB/IEC, assent also has to be obtained from the 
subject.
Prior to obtaining informed consent, information should be given in a language and at a level 
of complexity understandable to the subject and/or the subject’s parent/legal representative in 
both oral and written form by the investigator (or designee). Each subject and/or the subject’s 
parent/legal representative will have the opportunity to discuss the study and its alternatives 
with the investigator.
Prior to participation in the study, the written ICF should be signed and personally dated by 
the subject’s parent/legal representative, and by the person who conducted the informed 
consent discussion (investigator or designee). The subject’s parent/legal representative must 
receive a copy of the signed and dated ICF. As part of the consent process, the subject’s 
parent/legal representative must consent to direct access to the subject’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 USA must include the use of a Health Insurance 
Portability and Accountability Act Authorization form.
The subject may withdraw his/her consent to participate in the study at any time. A subject is 
considered as enrolled in the study when he/she and/or the subject’s parent/legal 
representative has signed the ICF. An eCRF must not be started, nor may any study specific 
procedure be performed for a given subject, without having obtained the subject’s 
parent/legal representative’s written consent and the subject’s assent to participate in the 
study.
14.2
Subject identification cards
Upon signing the Informed Consent and Assent form (as applicable), the subject or legal 
representative will be provided with a subject identification card in the language of the 
subject. The investigator will fill in the subject identifying information and medical 
emergency contact information. The investigator will instruct the subject to keep the card 
with him/her at all times.
14.3
Institutional Review Boards and IECs
The study will be conducted under the auspices of an IRB/IEC, as defined in local 
regulations, ICH-GCP, and in accordance with the ethical principles that have their origin in 
the Declaration of Helsinki.
The investigator/UCB will ensure that an appropriately constituted IRB/IEC that complies 
with the requirements of the current ICH-GCP version or applicable country-specific 
regulations will be responsible for the initial and continuing review and approval of the 
clinical study. Prior to initiation of the study, the investigator/UCB will forward copies of the 
protocol, ICF, Investigator’s Brochure, investigator’s curriculum vitae (if applicable), 
advertisement (if applicable), and all other subject-related documents to be used for the study 
to the IRB/IEC for its review and approval.
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 75 of 203
Before initiating a study, the investigator will have written and dated full approval from the 
responsible IRB/IEC for the protocol.
The investigator will also promptly report to the IRB/IEC all changes in the study, all 
unanticipated problems involving risks to human subjects or others, and any protocol 
deviations, to eliminate immediate hazards to subjects.
The investigator will not make any changes in the study or study conduct without IRB/IEC 
approval, except where necessary to eliminate apparent immediate hazards to the subjects. 
For minor changes to a previously approved protocol during the period covered by the 
original approval, it may be possible for the investigator to obtain an expedited review by the 
IRB/IEC as allowed.
As part of the IRB/IEC requirements for continuing review of approved studies, the 
investigator will be responsible for submitting periodic progress reports to the IRB/IEC 
(based on IRB/IEC requirements), at intervals appropriate to the degree of subject risk 
involved, but no less than once per year. The investigator should provide a final report to the 
IRB/IEC following study completion.
UCB (or its representative) will communicate safety information to the appropriate regulatory 
authorities and all active investigators in accordance with applicable regulatory requirements. 
The appropriate IRB/IEC will also be informed by the investigator or the sponsor, as 
specified by the applicable regulatory requirements in each concerned country. Where 
applicable, investigators are to provide the sponsor (or its representative) with evidence of 
such IRB/IEC notification.
14.4
Subject privacy
UCB staff (or designee) will affirm and uphold the subject’s confidentiality. Throughout this 
study, all data forwarded to UCB (or designee) will be identified only by the subject number.
The investigator agrees that representatives of UCB, its designee, representatives of the 
relevant IRB/IEC, or representatives of regulatory authorities will be allowed to review that 
portion of the subject’s primary medical records that directly concerns this study (including, 
but not limited to, laboratory test result reports, ECG reports, admission/discharge summaries 
for hospital admissions occurring during a subject’s study participation, and autopsy reports 
for deaths occurring during the study).
14.5
Protocol amendments
Protocol changes may affect the legal and ethical status of the study and may also affect the 
statistical evaluations of sample size and the likelihood of the study fulfilling its primary 
objective.
Significant changes to the protocol will only be made as an amendment to the protocol and 
must be approved by UCB, the IRB/IEC, and the regulatory authorities (if required), prior to 
being implemented.
15
FINANCE, INSURANCE, AND PUBLICATION
Insurance coverage will be handled according to local requirements.
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 76 of 203
Finance, insurance, and publication rights are addressed in the investigator and/or CRO 
agreements, as applicable.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 77 of 203
16
REFERENCES
Aicardi J. Syndromic classification in the management of childhood epilepsy. J Child Neurol. 
1994;9(Suppl 2):214-18.
Appleton R, Fichtner K, LaMoreaux L, Alexander J, Halsall G, Murray G, et al. Gabapentin 
as add-on therapy in children with refractory partial seizures: a 12-week, multicentre, 
double-blind, placebo-controlled study. Gabapentin Pediatric Study Group. Epilepsia. 
1999;40:1147-54.
Bayley N. Bayley Scales of Infant and Toddler Development. 3rd ed. San Antonio: Pearson 
Education Inc; 2006.
Bayley N. Bayley Scales of Infant Development. 2nd ed. San Antonio: The Psychological 
Corporation; 1993.
Beghi E, Sander JW. The natural history and prognosis of epilepsy. In: Engel J Jr, Pedley TA, 
editors. Epilepsy: A Comprehensive Textbook. 2nd ed. Philadelphia: Lippincott Williams and 
Wilkins; 2008. p. 65-70.
Columbia University Medical Center. Columbia-Suicide Severity Rating Scale (2008). 
http://www.cssrs.columbia.edu/. Accessed on 20 Mar 2012.
CPMP/ICH/135/95 Note for guidance on Good Clinical Practice (EMEA) Jul 2002.
Dichek B. Epilepsy: an ancient ailment that still eludes a cure. Scrip Magazine. 
1999;Feb:9-11.
Duchowny M, Pellock JM, Graf WD, Billard C, Gilman J, Casale E, et al. A 
placebo-controlled trial of lamotrigine add-on therapy for partial seizures in children.
Lamictal Pediatric Partial Seizure Study Group. Neurology. 1999;53:1724-31.
Elterman RD, Glauser TA, Wylie E, Reife R, Wu SC, Pledger G. A double-blind, 
randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children.
Topiramate YP Study Group. Neurology. 1999;52:1338-44.
Errington AC, Stöhr T, Heers C, Lees G. The investigational anticonvulsant lacosamide 
selectively enhances slow inactivation of voltage-gated sodium channels. Mol Pharmacol. 
2008;73:157-69. 
Glauser TA, Ayala R, Elterman RD, Mitchell WG, Van Orman CB, Gauer LJ, et al. on behalf 
of the N159 Study Group. Double-blind placebo-controlled trial of adjunctive levetiracetam 
in pediatric partial seizures. Neurology. 2006;66:1654-60.
Glauser TA, Nigro M, Sachdeo R, Pasteris LA, Weinstein S, Abou-Khalil B, et al. 
Adjunctive therapy with oxcarbazepine in children with partial seizures. The Oxcarbazepine 
Pediatric Study Group. Neurology. 2000;54:2237-44.
Hadjiloizou SM, Bourgeois BF. Antiepileptic drug treatment in children. Expert Rev 
Neurother. 2007;7:179-93.
Herman ST, Pedley TA. New options for the treatment of epilepsy. JAMA. 1998;280:693-4.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 78 of 203
Institute of Medicine. Epilepsy across the spectrum: promoting health and understanding. 
Washington, DC: The National Academies Press; 2012. 
Perucca E. Established antiepileptic drugs. Baillieres Clin Neurol. 1996;5:693-722.
Rheims S, Ryvlin P. Profile of perampanel and its potential in the treatment of partial 
onset seizures. Neuropsychiatr Dis Treat. 2013;9:629-37.
Sattler JM, Hoge RD. Assessment of children: behavioral, social, and clinical foundations. 
5th ed. La Mesa: Jerome M Sattler; 2006.
Shorvon SD. Drug treatment of epilepsy in the century of the ILAE: The second 50 years, 
1959-2009. Epilepsia. 2009;50(Suppl 3):93-130.
Varni JW, Limbers CA, Neighbors K, Schulz K, Lieu JE, Heffer RW, et al. The PedsQL™ 
Infant Scales: feasibility, internal consistency reliability, and validity in healthy and ill 
infants. Qual Life Res. 2011;20:45-55.
Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric Quality of 
Life Inventory version 4.0 generic core scales in healthy and patient populations. Med Care. 
2001;39:800-12. 
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
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17
APPENDICES
17.1
International Classification of Epileptic Seizures (1981)
Adapted from the International Classification of Epileptic Seizures (1981)
I.
Partial seizures (focal, local)
A. Simple partial seizures (consciousness not impaired)
1.
With motor signs
2.
With somatosensory or special sensory symptoms (simple hallucinations, eg, 
tingling, light flashes, buzzing)
3.
With autonomic symptoms or signs (including epigastric sensation, pallor, 
sweating, flushing, piloerection, and pupillary dilatation)
4.
With psychic symptoms (disturbance of higher cerebral function). These 
symptoms rarely occur without impairment of consciousness and are much more 
commonly experienced as complex partial seizures.
B. Complex partial seizures (with impairment of consciousness: may sometimes begin 
with simple symptomatology)
C. Partial seizures evolving to secondarily generalized seizures (this may be generalized 
tonic-clonic, tonic, or clonic)
II. Generalized seizures (convulsive or non-convulsive)
A.
Absence seizures
B.
Myoclonic seizures - Myoclonic jerks (single or multiple)
C.
Clonic seizures
D.
Tonic seizures
E.
Tonic-clonic seizures
F.
Atonic seizures - (Astatic)
Unclassified epileptic seizures
Includes all seizures that cannot be classified because of inadequate or incomplete data and 
some that defy classification in hitherto described categories. This includes some neonatal 
seizures, eg, rhythmic eye movements, chewing, and swimming movements.
Status epilepticus (prolonged partial or generalized seizures without recovery between 
attacks)
Commission on Classification and Terminology of the International League Against 
Epilepsy. Proposal for revised clinical and electroencephalographic classification of epileptic
seizures. Epilepsia. 1981;22:489-501.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 80 of 203
17.2
Protocol Amendment 1
Rationale for the amendment
The present Amendment has been issued following a Special Protocol Assessment performed 
by the USA FDA on SP0969, a Phase 3, multicenter, double-blind, randomized, 
placebo-controlled, parallel-group study to evaluate the efficacy and safety of LCM as 
adjunctive therapy in epilepsy subjects ≥4 years to <17 years of age with uncontrolled 
partial-onset seizures. Where applicable, the recommendations made by the FDA for SP0969 
have been incorporated into the current protocol. In addition, updates were made to improve 
the clarity of the protocol, particularly with regard to inclusion/exclusion criteria, additional 
assessments for safety and efficacy were added, and the number of sites was increased. The 
following major changes were made:
•
Dosing was changed to match SP0969 (based on subject weight).
•
Inclusion criteria for concomitant AEDs and VNS were modified to match with SP0969.
•
Subjects with primary generalized tonic-clonic seizures with a diagnosis of idiopathic 
generalized epilepsy were excluded. The effect of LCM in this population is planned to 
be investigated in a confirmatory study; therefore, this population will not be included in 
this exploratory study.
•
Exclusion criteria for felbamate and vigabatrin were modified.
•
The Behavior Rating Inventory of Executive Function was added as an additional safety 
assessment.
•
The Pediatric Quality of Life Inventory was added as an additional efficacy assessment.
•
Health care resource use was added as an efficacy variable.
•
The requirement to measure height was restricted to visits where a complete physical 
examination is required.
•
A new withdrawal criteria based on the use of rescue medication was added.
•
An additional assessment at end of titration was added for the Achenbach Child Behavior 
Checklist.
•
Orthostatic blood pressure and pulse assessments were added.
•
Concomitant and prohibited medications, and rescue medication were modified to match 
SP0969.
•
The terminology “syrup” was replaced with oral solution in the protocol.
•
Assessment time points for scales and questionnaires were modified.
•
Additional assessments for VNS assessments and urinalysis were added.
•
The number of sites was increased to 40.
•
Additional text was added clarifying which version of the C-SSRS should be used at 
study entry and for subjects turning 6 years of age.
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 81 of 203
•
Administrative changes were made; the CPM and safety reporting contact details were 
updated.
•
Typographical changes were made to improve clarity of wording.
Modifications and changes
Global changes
The following key changes were made throughout the protocol:
•
Dosing was changed, so that following titration the maximum doses by body weight 
were:
Subjects weighing 
≤30kg
LCM 12mg/kg/day
(oral solution)
Subjects weighing 
>30kg to ≤50kg
LCM 8mg/kg/day
(oral solution)
Subjects weighing 
>50kg
LCM 400mg/day
(tablet)
Specific changes
Change #1
SPONSOR DECLARATION
Clinical Project Manager
Has been changed to:
Clinical Project Manager
, RN, MSN
Change #2
STUDY CONTACT INFORMATION
Clinical Project Manager 
Name:
Address:
UCB BIOSCIENCES Inc. 
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
Phone:
Fax:
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 82 of 203
Has been changed to:
Clinical Project Manager 
Name:
, RN, MSN
Address:
UCB BIOSCIENCES Inc.
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
Phone:
Fax:
Change #3
Serious Adverse Event Reporting
Serious adverse event reporting (24h) and safety related issues
Fax
Europe and Rest of the World (except Japan): +32 2 386 24 21
USA: +1 800 880 6949
Canada: +1 877 582 8842
Email
Europe and Rest of the World (except Japan): GCSP@ucb.com
USA and Canada: GCSP@ucb.com
Has been changed to:
Serious adverse event reporting (24h)
Fax
Europe and Rest of the World (except Japan): +32 2 386 2421
USA: +1 800 880 6949
Canada: +1 877 582 8842
Email
Global (except Japan): DS_ICT@ucb.com
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 83 of 203
Change #4
LIST OF ABBREVIATIONS
The following abbreviations have been added:
BRIEF®-P/BRIEF®
Behavior Rating Inventory of Executive Function-Preschool
Version/Behavior Rating Inventory of Executive Function
FDA
Food and Drug Administration
HRQoL
Health-related Quality of Life
PedsQL™
Pediatric Quality of Life Inventory
Change #5
Section 1 SUMMARY
The primary variables in this study are changes in the count of generalized spike-wave 
discharges and change in days with any generalized seizures (absence, myoclonic, clonic, 
tonic, tonic-clonic, atonic, and partial evolving to secondarily generalized) from the Baseline 
Period to the Maintenance Period. Other variables to be assessed include efficacy, plasma 
concentrations, and other measures of safety.
Approximately 50 subjects will be enrolled in this study across approximately 30 sites in 
Europe, USA, and other regions as deemed necessary.
The study will begin with subject screening at Visit 1 and will consist of a 6-week 
prospective Baseline Period where seizure frequency will be captured through daily seizure 
diaries. At the end of the Baseline Period (completion of Visit 2), subjects will commence a 
4-week Titration Period. Subjects will initiate treatment with LCM at 3mg/kg/day (oral 
solution) or 100mg/day (tablets) per week and the dose can be titrated to a level to optimize 
tolerability and seizure control, not to exceed a 12mg/kg/day or 400mg/day dose, whichever 
is lower, based on body weight. At the end of the Titration Period (Visit 6), a 12-week 
Maintenance Period will begin. The end of the Maintenance Period will be Visit 9, or, if 
subjects withdraw early, the Early Termination Visit. Subjects may be eligible for 
participation in an additional open-label study (SP848) upon completion of the Maintenance 
Period and a minimum dose of 6mg/kg/day or 200mg/day. Subjects who do not complete the 
full 12 weeks of the Maintenance Period may still be eligible to enter the SP848 open-label 
study after consultation with the medical monitor. Subjects who choose not to participate in 
the additional open-label study, subjects who are not able to tolerate the lowest LCM dose 
(100mg/day for the tablet formulation or 3mg/kg/day for the syrup formulation), or subjects 
who are discontinuing due to other reasons will enter up to a 4-week Taper Period followed 
by a 1-week study drug-free Safety Period and Final Safety telephone contact.
Has been changed to:
The primary variables in this study are changes in the count of generalized spike-wave 
discharges and change in days with any generalized seizures (absence, myoclonic, clonic, 
tonic, tonic-clonic, atonic, and partial evolving to secondarily generalized) from the Baseline 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 84 of 203
Period to the Maintenance Period. The above variables reference partial seizures evolving 
to secondarily generalized seizures. While these partial seizures will be summarized as a 
part of the analysis, subjects must have a diagnosis of uncontrolled epilepsy with 
generalized seizures (Type II) according to the International Classification of Epileptic 
Seizures (1981) (see Section 17.1) to possibly be eligible for study participation. In 
addition to the Type II seizures, subjects with a current diagnosis of mixed seizure 
disorder(s), including both Type I and Type II seizures, are also eligible. Subjects with 
exclusively absence (Type IIA1) or atypical absence (Type IIA2) seizures are not 
eligible. Subjects with primary generalized tonic-clonic seizures with a diagnosis of 
idiopathic generalized epilepsy are also not eligible for this study as there is a 
confirmatory (Phase 3) study evaluating this seizure type. Other variables to be assessed 
include measures of efficacy, plasma concentrations, and other measures of safety.
Approximately 50 subjects will be enrolled in this study across approximately 40 sites in 
Europe, USA, and other regions as deemed necessary.
The study will begin with subject screening at Visit 1 and will consist of a 6-week 
prospective Baseline Period where seizure frequency will be captured through daily seizure 
diaries. At the end of the Baseline Period (completion of Visit 2), subjects will commence a 
4-week Titration Period, where subjects will initiate treatment with LCM. Subjects 
weighing ≤30kg will begin treatment on LCM oral solution (syrup) 3mg/kg/day, subjects 
weighing >30kg to ≤50kg will begin treatment on LCM oral solution 2mg/kg/day, and 
subjects weighing >50kg will begin treatment on LCM tablets 100mg/day (subjects 
weighing >50kg who are unable or unwilling to swallow tablets can also be dispensed 
LCM oral solution). The dose will be titrated to a level to optimize tolerability and 
seizure control, not to exceed 12mg/kg/day for subjects weighing ≤30kg, or 8mg/kg/day 
for subjects weighing >30kg to ≤50kg, and 400mg/day (tablets/oral solution) in subjects 
weighing >50kg. At the end of the Titration Period (Visit 6), a 12-week Maintenance Period 
will begin. Subjects must titrate to at least 6mg/kg/day for subjects weighing ≤30kg, 
4mg/kg/day for subjects weighing >30kg to ≤50kg, or 200mg/day (tablets/oral solution) 
for subjects weighing >50kg in order to enter the Maintenance Period.
The end of the Maintenance Period will be Visit 9, or, if subjects withdraw early, the Early 
Termination Visit. Subjects may be eligible for participation in an additional open-label study 
(SP848) if they have completed the Maintenance Period and a minimum dose of 6mg/kg/day 
for subjects weighing ≤30kg, 4mg/kg/day for subjects weighing >30kg to ≤50kg, and 
200mg/day (tablets/oral solution) in subjects weighing >50kg. Subjects who do not 
complete the full 12 weeks of the Maintenance Period may still be eligible to enter the SP848 
open-label study after consultation with the medical monitor. Subjects who choose not to 
participate in the additional open-label study, subjects who are only able to tolerate the 
lowest LCM dose (100mg/day for the tablet formulation, 3mg/kg/day or 2mg/kg/day for the 
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 85 of 203
Change #6
Section 2 INTRODUCTION
Lacosamide has been approved as adjunctive therapy in the treatment of partial-onset seizures 
with or without secondary generalization in patients 16 years of age and older in the EU (oral 
tablets, oral solution [syrup], and solution for intravenous [iv] infusion) and as adjunctive 
therapy in the treatment of partial-onset seizures in patients 17 years of age and older in the 
USA (oral tablets, oral solution, and solution for iv infusion). The oral solution (syrup) and 
the film-coated tablet formulations are suitable for oral administration to pediatric patients.
Bioequivalence has been shown between the tablet and oral solution (syrup) formulations, 
comparing 2 tablets of LCM 100mg and the oral solution (syrup) containing LCM 200mg, 
after single-dose administration in healthy subjects. The PK of LCM and its major 
metabolite, SPM 12809 (O-desmethyl-LCM), in plasma, urine, and saliva were identical or 
very similar after single oral doses of LCM 200mg administered as tablets or as oral solution 
(syrup).
UCB has completed a Phase 2, open-label safety study (SP0961) of adjunctive LCM 
treatment for primary generalized tonic-clonic seizures in adult subjects with idiopathic 
generalized epilepsy. The results of SP0961 showed reductions in primary generalized 
tonic-clonic seizure frequency and myoclonic seizure days, with a small reduction in absence 
seizure days. A minority of subjects (~10%) showed an increase in absence seizures (reported 
as TEAEs) that, in this uncontrolled study, cannot be distinguished between the drug versus 
the natural course of the disease. The AE profile was similar to that of adjunctive LCM for 
the treatment of subjects with partial-onset seizures, with the exception of seizure-related 
AEs.
Has been changed to:
Lacosamide has been approved as adjunctive therapy in the treatment of partial-onset seizures 
with or without secondary generalization in patients 16 years of age and older in the EU (oral 
tablets, oral solution, and solution for intravenous [iv] infusion) and as adjunctive therapy in 
the treatment of partial-onset seizures in patients 17 years of age and older in the USA (oral 
tablets, oral solution, and solution for iv infusion). The oral solution and the film-coated 
tablet formulations are suitable for oral administration to pediatric patients.
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 subjects. The PK of LCM and its major metabolite, 
SPM 12809 (O-desmethyl-LCM), in plasma, urine, and saliva were identical or very similar 
after single oral doses of LCM 200mg administered as tablets or as oral solution.
UCB has completed a Phase 2, open-label safety study (SP0961) of adjunctive LCM 
treatment for primary generalized tonic-clonic seizures in subjects ≥ 16 years of age with 
idiopathic generalized epilepsy. The results of SP0961 showed reductions in primary 
generalized tonic-clonic seizure frequency and myoclonic seizure days, with a small 
reduction in absence seizure days. A minority of subjects (~10%) showed an increase in 
absence seizures (reported as TEAEs) that, in this uncontrolled study, cannot be distinguished 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 86 of 203
between the drug versus the natural course of the disease. The AE profile was similar to that 
of adjunctive LCM for the treatment of subjects with partial-onset seizures, with the 
exception of seizure-related AEs.
Change #7
Section 4 STUDY VARIABLES
The following text has been added:
The variables below reference partial seizures evolving to secondarily generalized 
seizures. While these partial seizures will be summarized as a part of the analysis, 
subjects must meet eligibility criteria to be applicable for the study (see inclusion 
criterion 4 and exclusion criteria 5 and 6 for applicable subjects).
Change #8
Section 4.1.3 Other variables assessing safety
Behavioral and cognition assessment (Achenbach Child Behavior Checklist [CBCL/1½-5 or
CBCL/6-18]) for pediatric subjects ≥18 months of age
Has been changed to:
Behavioral assessment (Achenbach Child Behavior Checklist [CBCL/1½-5 or CBCL/6-18]) 
for pediatric subjects ≥18 months of age
Assessment of cognitive function (Behavior Rating Inventory of Executive 
Function-Preschool Version for subjects ≥2 years to <5 years of age [BRIEF®-P] or the 
Behavior Rating Inventory of Executive Function [BRIEF®] for subjects ≥5 years of 
age)
Change #9
Section 4.2 Preliminary efficacy variables
The following assessments have been added:
Change in quality of life assessment (Pediatric Quality of Life Inventory [PedsQL™]) 
for subjects ≥1 month to ≤18 years of age
Health care resource use (concomitant AEDs, medical procedures, health care provider 
consultations not related to study, hospitalizations not related to study)
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 87 of 203
Change #10
Section 5.1 Study description
SP0966 is a Phase 2, multicenter, open-label exploratory study designed to assess the safety 
and preliminary efficacy of oral LCM as adjunctive therapy for epilepsy syndromes 
associated with generalized seizures in pediatric subjects ≥1 month to <18 years of age.
Initially, only subjects ≥4 years of age will be included in this study. Once the LCM dose 
range has been defined in subjects <4 years of age, enrollment of subjects in the younger 
cohort will begin.
Subjects should have a diagnosis of uncontrolled epilepsy with generalized seizures (Type II) 
according to the International Classification of Epileptic Seizures (1981), see Section 17.1. 
Subjects with exclusively typical absence (Type IIA1) or atypical absence (Type IIA2) 
seizures are not eligible. Diagnosis should have been established by clinical history and an 
EEG with generalized spike-wave discharges.
The study treatment is LCM in either the oral syrup formulation or tablet formulation. The 
formulation of LCM to be administered will be decided by the investigator and the subject. 
Subjects will not be randomized, but all subjects who sign the informed consent form (ICF) at 
Visit 1 will be assigned a unique identification number. 
The study will begin with subject screening at Visit 1 and will consist of a 6-week 
prospective Baseline Period where seizure frequency will be captured. Subjects/caregivers 
will maintain a diary to record daily seizure activity from Visit 1 until the end of the study. 
The subject diary will capture seizure type and seizure frequency information. If all inclusion 
criteria are met and no exclusion criteria are met, the subject will begin a 4-week Titration 
Period starting at Visit 2. Subjects will be asked to return to the clinic on the morning of the 
day prior to Visit 2 to begin 24-hour ambulatory EEG recordings. Subjects will initiate 
treatment with LCM at 3mg/kg/day (oral solution) or 100mg/day (tablets) per week and the 
dose can be titrated to a level to optimize tolerability and seizure control, not to exceed a 
12mg/kg/day or 400mg/day dose, whichever is lower, based on body weight. 
At the end of the Titration Period (Visit 6), a 12-week Maintenance Period will begin. 
Subjects will return to the clinic (on the morning of the day prior to the scheduled visit) at 
Visit 6 and Visit 9 or Early Termination for 24-hour ambulatory EEG recordings for 
evaluation of spike-wave discharges. The end of the Maintenance Period will be Visit 9, or, if 
subjects withdraw early, the Early Termination Visit. Subjects may be eligible for 
participation in the additional open-label study (SP848) upon completion of the Maintenance 
Period and a minimum dose of 6mg/kg/day or 200mg/day. Subjects who do not complete the 
full 12 weeks of the Maintenance Period may still be eligible to enter the SP848 open-label 
study after consultation with the medical monitor. Subjects who choose not to participate in 
the open-label study, subjects who are not able to tolerate the lowest LCM dose (100mg/day 
for the tablet formulation or 3mg/kg/day for the syrup formulation), or subjects who are 
discontinuing due to other reasons will enter up to a 4-week Taper Period followed by a 
1-week study drug-free Safety Period and Final Safety telephone contact. 
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 88 of 203
Has been changed to:
SP0966 is a Phase 2, multicenter, open-label exploratory study designed to assess the safety 
and preliminary efficacy of oral LCM as adjunctive therapy for epilepsy syndromes 
associated with generalized seizures in pediatric subjects ≥1 month to <18 years of age.
Initially, only subjects ≥4 years of age will be included in this study. Once the LCM dose 
range has been defined in subjects <4 years of age, enrollment of subjects in the younger 
cohort will begin.
Subjects should have a current diagnosis of epilepsy with generalized seizures (Type II) 
according to the International Classification of Epileptic Seizures (1981), see Section 17.1.
The diagnosis should have been established by clinical history and an EEG with 
generalized spike-wave discharges. In addition to the Type II seizures, subjects with a 
current diagnosis of mixed seizure disorder(s), including both Type I and Type II 
seizures, are also eligible. Subjects with exclusively absence (Type IIA1) or atypical 
absence (Type IIA2) seizures are not eligible. Subjects with primary generalized 
tonic-clonic seizures with a diagnosis of idiopathic generalized epilepsy are also not 
eligible for this study as there is a confirmatory (Phase 3) study evaluating this seizure 
type.
The study treatment is LCM in either the oral solution formulation or tablet formulation. The 
formulation of LCM to be administered is based on the weight of the subject. Only 
subjects weighing >50kg who are able and willing to swallow tablets may be dispensed 
LCM tablets.
Subjects will not be randomized, but all subjects who sign the informed consent form (ICF) at 
Visit 1 will be assigned a unique identification number. 
The study will begin with subject screening at Visit 1 and will consist of a 6-week 
prospective Baseline Period where seizure frequency will be captured. Subjects/caregivers 
will maintain a diary to record daily seizure activity from Visit 1 until the end of the study. 
The subject diary will capture seizure type and seizure frequency information. If all inclusion 
criteria are met and no exclusion criteria are met, the subject will begin a 4-week Titration 
Period starting at Visit 2. Subjects will be asked to return to the clinic on the morning of the 
day prior to Visit 2 to begin 24-hour ambulatory EEG recordings. Subjects will initiate 
treatment with LCM oral solution at 2mg/kg/day or 3mg/kg/day, or LCM tablets at 
100mg/day based on body weight. The dose will be titrated to a level to optimize 
tolerability and seizure control, not to exceed 12mg/kg/day for subjects weighing ≤30kg, 
or 8mg/kg/day for subjects weighing >30kg to ≤50kg, and 400mg/day (tablets/oral 
solution) in subjects weighing >50kg. Subjects will increase the LCM dose in a stepwise 
fashion on a weekly basis to optimize tolerability and seizure control. During the 
Titration period only, one back-titration step is permitted; once the dose of LCM has 
been back-titrated, the dose cannot be increased for the duration of the study (see 
Figure 5-1 and Figure 5-2).
If a subject does not achieve or require the maximum dose level (8mg/kg/day, 
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until the end of the Titration Period. The Titration Period will last 4 weeks, regardless 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 89 of 203
of the doses administered. Subjects who are not able to tolerate the minimum required 
dose (at least 6mg/kg/day for subjects weighing ≤30kg, 4mg/kg/day for subjects 
weighing >30kg to ≤50kg, or 200mg/day [tablets/oral solution] for subjects weighing 
>50kg) of LCM (even after back-titration) will be withdrawn from the study. Study 
medication doses will be titrated according to the schedules presented in Table 7-1.
The maximum LCM dose is not to exceed 12mg/kg/day (oral solution) for subjects 
weighing ≤30kg, 8mg/kg/day (oral solution) for subjects weighing >30kg to ≤50kg, and 
400mg/day (tablets/oral solution) in subjects weighing >50kg.
At the end of the Titration Period (Visit 6), a 12-week Maintenance Period will begin. 
Subjects must titrate to at least 6mg/kg/day for subjects weighing ≤30kg, 4mg/kg/day 
for subjects weighing >30kg to ≤50kg, or 200mg/day (tablets/oral solution) for subjects 
weighing >50kg in order to enter the Maintenance Period. Subjects will return to the 
clinic (on the morning of the day prior to the scheduled visit) at Visit 6 and Visit 9 or Early 
Termination for 24-hour ambulatory EEG recordings for evaluation of spike-wave 
discharges. The end of the Maintenance Period will be Visit 9, or, if subjects withdraw early, 
the Early Termination Visit. Subjects may be eligible for participation in the additional
open-label study (SP848) upon completion of the Maintenance Period and a minimum dose 
of 6mg/kg/day for subjects weighing ≤30kg, 4mg/kg/day for subjects weighing >30kg to 
≤50kg, and 200mg/day (tablets/oral solution) in subjects weighing >50kg. Subjects who 
do not complete the full 12 weeks of the Maintenance Period may still be eligible to enter the 
SP848 open-label study after consultation with the medical monitor. Subjects who choose not
to participate in the open-label study, subjects who are only able to tolerate the lowest LCM 
dose (100mg/day for the tablet formulation, 3mg/kg/day or 2mg/kg/day for the oral 
solution formulation), or subjects who are discontinuing due to other reasons will enter up 
to a 4-week Taper Period followed by a 1-week study drug-free Safety Period and Final 
Safety telephone contact. Dosing schedules for the Taper Period are provided in 
Table 7-2, Table 7-3, and Table 7-4.
Change #11
Section 5.1.1 Study duration per subject
The study will consist of a 6-week prospective Baseline Period, followed by a 4-week 
Titration Period, and a 12-week Maintenance Period. Subjects may be eligible to enter an 
additional open-label study (SP848) after completion of the Maintenance Period, or, if they
do not continue in the open-label study, subjects will enter up to a 4-week Taper Period 
followed by a 1-week study drug-free Safety Period and Final Safety telephone contact. The 
total study duration for a subject will be up to a maximum of 21 weeks. 
Has been changed to:
The study will consist of a 6-week prospective Baseline Period, followed by a 4-week 
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additional open-label study (SP848) after completion of the Maintenance Period. Subjects 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 90 of 203
enter the SP848 open-label study after consultation with the medical monitor. Subjects 
who do not continue in the open-label study will enter up to a 4-week Taper Period followed 
by a 1-week study drug-free Safety Period and Final Safety telephone contact. The total study 
duration for a subject will be up to a maximum of 27 weeks.
Change #12
Section 5.1.3 Anticipated regions and countries
This study will be conducted at approximately 30 sites in Europe, USA, and other regions as 
deemed necessary.
Has been changed to:
This study will be conducted at approximately 40 sites in Europe, USA, and other regions as 
deemed necessary.
Change #13
Section 5.2 Schedule of study assessments
Table 5-1 Schedule of study assessments (Baseline Period, Titration Period, 
Maintenance Period, End of Study Period and Unscheduled Visit)
The following assessments have been modified/added:
•
Vital signs: orthostatic assessments were added
•
Urinalysis was added at Visit 9/ET
•
The Behavior Rating Inventory of Executive Function (BRIEF-P/BRIEF) was added 
at Visit 2 and Visit 9/ET
•
The Pediatric Quality of Life Inventory (PedsQL) was added at Visit 2 and Visit 
9/ET
•
The Achenbach Child Behavior Checklist was added at Visit 6
•
The Bayley-III and Achenbach Child Behavior Checklist were moved from Visit 1 to 
Visit 2
•
Assessment of VNS changes was added at all clinic visits
•
Health care resource use was added at all clinic visits
The following abbreviations have been added:
•
BRIEF-P/BRIEF=Behavior Rating Inventory of Executive Function-Preschool
Version/Behavior Rating Inventory of Executive Function
•
PedsQL=Pediatric Quality of Life Inventory
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 91 of 203
The following footnotes have been modified/added:
a
Unscheduled Visits may be performed at any time after Visit 1, at the discretion of the 
investigator. In addition to the required assessments indicated in the schedule above, 
further assessments can be completed as needed and may include ECG, laboratory tests, 
physical examination, neurological examination, etc.
b
The recommended Taper Period duration for subjects taking the tablet formulation is 2 
weeks, but a slower taper over 4 weeks may be permitted if medically necessary. The 
duration of the Taper Period for the oral solution formulation is 4 weeks. The End of 
Taper Visit will occur at the end of the last week of the Taper Period.
c
At the end of Visit 9 or at ET, all subjects who complete the Maintenance Period and 
whose daily dose was at least 6mg/kg/day for subjects weighing ≤30kg, 4mg/kg/day 
for subjects weighing >30kg to ≤50kg, and 200mg/day (tablets/oral solution) in 
subjects weighing >50kg will be offered the opportunity to enroll in an additional open-
label extension study, SP848. Visit 9 or the ET Visit of SP0966 will also serve as Visit 1 
for SP848. Subjects who do not complete the full 12 weeks of the Maintenance Period 
may still be eligible to enter the SP848 open-label study after consultation with the 
medical monitor. Subjects who do not continue in the open-label extension study will 
complete the End of Study procedures that include up to a 4-week LCM taper followed 
by a 1-week Safety Follow-up Period and Final Safety telephone contact.
f
Height will only be recorded at study visits where a complete physical examination is 
performed. Height is not required at an Unscheduled Visit.
o
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s
For subjects entering Taper Period and not SP848.
Change #14
Section 5.3 Schematic diagram
Figure 5-2 presents a schematic diagram of the LCM syrup dosing and taper schedule.
Has been changed to:
Figure 5-2 presents a schematic diagram of the LCM oral solution dosing and taper 
schedule.
Figure 5-1 Schematic diagram - LCM tablet dosing and taper schedule
The following modifications have been made to the Maintenance Period:
•
Solid lines were added to indicate that the 200, 300 and 400mg/day dose can be 
carried through to the Maintenance Period; with no further dose modifications. The 
label “400mg/day” was removed from the Maintenance Period.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 92 of 203
Figure 5-2 Schematic diagram - LCM syrup dosing and taper schedule
The Figure title has been changed to:
•
Figure 5-2 Schematic diagram - LCM oral solution dosing and taper schedule
The following titration steps have been added:
•
3mg/kg/day or 2mg/kg/day
•
6mg/kg/day or 4mg/kg/day
•
9mg/kg/day or 6mg/kg/day
•
12mg/kg/day or 8mg/kg/day
The following modifications have been made to the Maintenance Period:
•
Solid lines were added to indicate that the 6mg/kg/day or 4mg/kg/day, 9mg/kg/day 
or 6mg/kg/day and 12mg/kg/day or 8mg/kg/day dose can be carried through to the 
Maintenance Period; with no further dose modifications. The label “12mg/kg/day”
was removed from the Maintenance Period.
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•
9mg/kg/day or 6mg/kg/day 
•
6mg/kg/day or 4mg/kg/day
•
3mg/kg/day or 2mg/kg/day
Change #15
Section 5.4 Rationale for study design and selection of dose
Based on the currently available LCM pediatric safety and PK data from SP847 and SP1047, 
as well as on information available in the medical literature, the dosing recommendations for 
SP0966 are that a maximum dose of 12mg/kg/day in SP0966 should aim to achieve LCM 
plasma concentrations equivalent to the average steady-state LCM plasma concentration 
reached after a LCM 400mg/day dose administration in adult studies, which is approximately 
8μg/mL.
Has been changed to:
Based on the currently available LCM pediatric safety and PK data from SP847 and SP1047, 
as well as on information available in the medical literature, the dosing recommendations for 
SP0966 are as follows:
•
LCM dosing should aim to achieve LCM plasma concentrations equivalent to the 
average steady-state LCM plasma concentration reached after a LCM 400mg/day 
dose administration in adult studies, which is approximately 8μg/mL.
•
A weight-based dosing scheme is recommended:
−
Subjects ≤30kg: LCM 12mg/kg/day (oral solution)
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 93 of 203
−
Subjects >30kg to ≤50kg: LCM 8mg/kg/day (oral solution, up to a maximum of 
LCM 400mg/day)
−
Subjects weighing >50kg: 400mg/day (tablets/oral solution)
Change #16
Section 6.1 Inclusion criteria
4. Subject has a diagnosis of uncontrolled epilepsy with generalized seizures (Type II) 
according to the International Classification of Epileptic Seizures (1981) (see 
Section 17.1). The underlying epilepsy syndrome should be documented. Subjects with 
exclusively absence (Type IIA1) or atypical absence (Type IIA2) seizures are not eligible. 
Diagnosis should have been established by clinical history and an EEG with generalized 
spike-wave discharges. Documentation of the EEG finding of generalized spike waves 
(EEG recording or a report) is required. The EEG should have been performed no more 
than 18 months prior to Visit 1 (with no change to diagnosis or seizures during this time).
6. Subject has been maintained on a stable dose regimen of 1 to 3 marketed AEDs for at 
least 28 days prior to Visit 1 and with or without additional concurrent stable VNS. Vagus 
nerve stimulation must have been in place for at least 6 months prior to study entry with 
constant settings for at least 1 week prior to Visit 1
Has been changed to:
4. Subject has a diagnosis of uncontrolled epilepsy with generalized seizures (Type II) 
according to the International Classification of Epileptic Seizures (1981) (see 
Section 17.1). The underlying epilepsy syndrome should be documented. Diagnosis 
should have been established by clinical history and an EEG with generalized spike-
wave discharges. Documentation of the EEG finding of generalized spike waves (EEG 
recording or a report) is required. The EEG should have been performed no more than 18 
months prior to Visit 1 (with no change to diagnosis or seizure types during this time).
6. Subject is on a stable dosage regimen of 1 to 3 AEDs. The daily dosage regimen of 
concomitant AED therapy must be kept constant for a period of at least 4 weeks 
prior to the Baseline Period.
7. Vagal nerve stimulation is allowed and will not be counted as a concomitant AED. 
Vagal nerve stimulation (implanted for at least 6 months and stable for at least 
4 weeks before Visit 1) must be kept stable during the Baseline Period and the 
Maintenance Period.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 94 of 203
Change #17
Section 6.2 Exclusion criteria
The following exclusion criterion has been added:
6. Subject has primary generalized tonic-clonic seizures with a diagnosis of idiopathic 
generalized epilepsy.
The following exclusion criteria have been modified:
8. Subject has a known hypersensitivity to any components of the investigational medicinal 
product (IMP). Subject has a medical condition that could reasonably be expected to 
interfere with drug absorption, distribution, metabolism, or excretion.
20. Subject has been treated with vigabatrin or felbamate for at least 12 months prior to 
entering the study and has experienced any toxicity issues with these treatments. Note: 
any subject who is currently treated with vigabatrin or felbamate, and has received 
vigabatrin or felbamate for a period of less than 12 months, is excluded from the study. 
Subjects who have received vigabatrin in the past must have completed vigabatrin therapy 
at least 6 months prior to study entry. Subjects must have documentation of an assessment 
for visual field defects prior to study entry or documentation of why visual field testing
cannot be performed.
Have been changed to:
9. Subject has a known hypersensitivity to any components of the investigational 
medicinal product (IMP). 
10. Subject has a medical condition that could reasonably be expected to interfere with 
drug absorption, distribution, metabolism, or excretion.
22. Subject has been treated with vigabatrin and experienced any vision loss. Subjects 
who have received vigabatrin in the past must have documentation of an assessment 
for vision loss prior to study entry or documentation of why visual field testing 
cannot be performed.
23. Subject has been treated with felbamate and has experienced any serious toxicity 
issues (defined as liver failure, aplastic anemia) with this treatment. Subjects treated 
with felbamate for less than 12 months are excluded. Note: any subject who has been 
treated with felbamate for at least 12 months and has not experienced serious 
toxicity issues is eligible.
Change #18
Section 6.3 Withdrawal criteria
All subjects discontinuing treatment with LCM for any reason should taper off LCM. It is 
recommended that the dosage be tapered off in weekly decrements of 3mg/kg/day (oral 
solution) or 200mg/day (tablet) (see Section 7.2). A slow taper 100mg/day (tablet) is 
permitted if medically necessary. Whenever possible, these cases should be discussed with 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 95 of 203
the medical monitor prior to withdrawing the subject from the study, especially in cases in 
which exit criteria have been met.
Has been changed to:
All subjects discontinuing treatment with LCM for any reason should taper off LCM. It is 
recommended that the dosage be tapered off in weekly decrements of 2 mg/kg/day or
3mg/kg/day (oral solution) or 200mg/day (tablet) (see Section 7.2). A slower taper is 
permitted if medically necessary. Whenever possible, these cases should be discussed with 
the medical monitor prior to withdrawing the subject from the study, especially in cases in 
which exit criteria have been met.
The following withdrawal criterion has been added:
10. Subject requires the use of rescue medication in excess of that permitted by the 
protocol.
Change #19
Section 7.2 Treatment(s) to be administered
At the end of the Baseline Period (completion of Visit 2), subjects who meet the eligibility 
criteria will commence a 4-week Titration Period. Subjects will initiate treatment with LCM 
at 3mg/kg/day (oral solution) or 100mg/day (tablets) per week, and the dose can be titrated to 
a level to optimize tolerability and seizure control, not to exceed a 12mg/kg/day or 
400mg/day dose, whichever is lower, based on body weight.
The planned doses for each week of the Titration Period for subjects taking the LCM syrup 
and tablet formulations are displayed in Table 7-1.
Table 7-1
Lacosamide dose titration during the Titration Period
Dose
Formulation
Week 1
Week 2
Week 3
Week 4
Syrup
3mg/kg/day
6mg/kg/day
9mg/kg/day
12mg/kg/day
Tablet
100mg/day
200mg/day
300mg/day
400mg/day
Based on tolerability, a 1-step back-titration of LCM 3mg/kg/day or 100mg/day, depending 
on the formulation is allowed during the Titration Period. Only 1 back-titration is permitted 
and once the dose of LCM has been back-titrated, the dose cannot be increased later. If a 
subject does not achieve the maximum dose level (12mg/kg/day or 400mg/kg/day), then the 
highest dose achieved will be maintained until the end of the Titration Period. The Titration 
Period will last 4 weeks, regardless of the doses administered. Subjects who are not able to 
tolerate LCM (even after back-titration) will be withdrawn from the study.
At the end of the Titration Period (Visit 6), a 12-week Maintenance Period will begin. 
Subjects will enter the Maintenance Period at the LCM dose achieved at the end of the 
Titration Period; up to a maximum of 12mg/kg/day for the syrup formulation or 400mg/day 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 96 of 203
for the tablet formulation. No dose modification is permitted during the Maintenance Period. 
Subjects who require a change in dose during the Maintenance Period will be withdrawn 
from the study. 
Subjects may be eligible for participation in the additional open-label study (SP848) upon 
completion of the Maintenance Period and a minimum dose of 6mg/kg/day or 200mg/day. 
Subjects will begin SP848 on the LCM dose they were taking in the Maintenance Period in 
SP0966. Subjects who do not complete the full 12 weeks of the Maintenance Period may still
be eligible to enter the SP848 open-label study after consultation with the medical monitor.
Subjects who choose not to participate in the open-label study, subjects who are not able to 
tolerate the lowest LCM dose (100mg/day for the tablet formulation or 3mg/kg/day for the 
syrup formulation), or subjects who are discontinuing due to other reasons will enter up to a 
4-week Taper Period followed by a 1-week study drug-free Safety Period and Final Safety 
telephone contact. The doses to be used during the Taper Period and the duration of the Taper 
Period will depend on the dose maintained during the Maintenance Period. For subjects 
taking the LCM syrup, weekly decrements of 3mg/kg/day are recommended during the Taper 
Period. For subjects taking the LCM tablets, a weekly decrement of 200mg/day per week 
during the Taper Period is recommended. 
Table 7-2 and Table 7-3 display the recommended LCM dose reductions during the Taper 
Period for the LCM syrup and tablet formulations, respectively. 
Table 7-2
Recommended LCM dose taper for oral solution (syrup) formulation
Maximum LCM dose 
maintained
Taper schedule
Week 17
Week 18
Week 19
Week 20
12mg/kg/day
9mg/kg/day
6mg/kg/day
3mg/kg/day
0
9mg/kg/day
6mg/kg/day
3mg/kg/day
0
-
6mg/kg/day
3mg/kg/day
0
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3mg/kg/day
0
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-
-
LCM=lacosamide
Table 7-3
Recommended LCM dose taper for tablet formulation
Maximum LCM dose maintained
Taper schedule
Week 17
Week 18
400mg/day
200mg/day
0
300mg/day
100mg/day
0
200mg/day
0
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 97 of 203
All subjects discontinuing treatment with LCM for any reason should taper off LCM. It is 
recommended that the dosage be tapered off in weekly decrements of 3mg/kg/day (oral 
solution) or 200mg/day (tablet). A slow taper 100mg/day over 4 weeks (tablet) is permitted if 
medically necessary. Whenever possible, these cases should be discussed with the medical 
monitor prior to withdrawing the subject from the study, especially in cases in which exit 
criteria have been met. In case of an emergency, a faster taper is permitted after discussion 
with the medical monitor, whenever possible.
If subjects discontinue prematurely from the study, an Early Termination Visit will occur
where subjects will be instructed to taper their LCM dose as appropriate. These subjects will 
not be eligible to participate in the open-label study (SP848), unless the medical monitor has 
approved their transition to SP848.
Has been changed to:
Study medication will be administered orally bid (at approximately 12-hour intervals in 
the morning and in the evening).
At the end of the Baseline Period (completion of Visit 2), subjects who meet the eligibility 
criteria will commence a 4-week Titration Period.
As described in Section 5.1, subjects will initiate treatment with LCM oral solution at 
2mg/kg/day or 3mg/kg/day, or LCM tablets at 100mg/day based on body weight. The 
dose will be titrated to a level to optimize tolerability and seizure control, not to exceed 
12mg/kg/day for subjects weighing ≤30kg, or 8mg/kg/day for subjects weighing >30kg to 
≤50kg, and 400mg/day (tablets/oral solution) in subjects weighing >50kg. Subjects will 
increase the LCM dose in a stepwise fashion on a weekly basis to optimize tolerability 
and seizure control. During the Titration period only, one back-titration step is 
permitted; once the dose of LCM has been back-titrated, the dose cannot be increased 
for the duration of the study (see Figure 5-1 and Figure 5-2). 
If a subject does not achieve or require the maximum dose level (8mg/kg/day, 
12mg/kg/day, or 400mg/kg/day), then the highest optimized dose will be maintained 
until the end of the Titration Period. The Titration Period will last 4 weeks, regardless 
of the doses administered. Subjects who are not able to tolerate the minimum required 
dose (at least 6mg/kg/day for subjects weighing ≤30kg, 4mg/kg/day for subjects 
weighing >30kg to ≤50kg, or 200mg/day [tablets/oral solution] for subjects weighing 
>50kg) of LCM (even after back-titration) will be withdrawn from the study. Study 
medication doses will be titrated according to the schedules presented in Table 7-1.
The maximum LCM dose is not to exceed 12mg/kg/day (oral solution) for subjects 
weighing ≤30kg, 8mg/kg/day (oral solution) for subjects weighing >30kg to ≤50kg, and 
400mg/day (tablets/oral solution) in subjects weighing >50kg.
The planned doses for each week of the Titration Period for subjects taking the LCM oral 
solution and tablet formulations are displayed in Table 7-1.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 98 of 203
Table 7-1
Lacosamide dose titration during the Titration Period
Week
Study Medication Dose
Subjects weighing 
≤30kg
LCM 12mg/kg/day
(oral solution)
Subjects weighing 
>30kg to ≤50kg
LCM 8mg/kg/day
(oral solution)
Subjects weighing 
>50kg
LCM 400mg/day
(tablet)
1
3mg/kg/day
2mg/kg/day
100mg/day
2
6mg/kg/day
4mg/kg/day
200mg/day
3
9mg/kg/day
6mg/kg/day
300mg/day
4
12mg/kg/day
8mg/kg/day
400mg/day
At the end of the Titration Period (Visit 6), a 12-week Maintenance Period will begin. 
Subjects must titrate to at least 6mg/kg/day for subjects weighing ≤30kg, 4mg/kg/day 
for subjects weighing >30kg to ≤50kg, or 200mg/day (tablets/oral solution) for subjects 
weighing >50kg in order to enter the Maintenance Period. Subjects will enter the 
Maintenance Period at the LCM dose achieved at the end of the Titration Period. No dose 
modification is permitted during the Maintenance Period. Subjects who require a change in 
dose during the Maintenance Period will be withdrawn from the study. Subjects who require 
a change in formulation during the Maintenance Period should consult the medical 
monitor to assess if the subject can continue in the study.
Subjects may be eligible for participation in the additional open-label study (SP848) upon 
completion of the Maintenance Period and a minimum dose of 6mg/kg/day for subjects 
weighing ≤30kg, 4mg/kg/day for subjects weighing >30kg to ≤50kg, and 
200mg/day (tablets/oral solution) in subjects weighing >50kg. Subjects will begin SP848 
on the LCM dose they were taking in the Maintenance Period in SP0966. Subjects who do 
not complete the full 12 weeks of the Maintenance Period may still be eligible to enter the 
SP848 open-label study after consultation with the medical monitor.
Subjects who choose not to participate in the open-label study, subjects who are only able to 
tolerate the lowest LCM dose (100mg/day for the tablet formulation, 3mg/kg/day or 
2mg/kg/day for the oral solution formulation), or subjects who are discontinuing due to 
other reasons will enter up to a 4-week Taper Period followed by a 1-week study drug-free 
Safety Period and Final Safety telephone contact. The doses to be used during the Taper 
Period and the duration of the Taper Period will depend on the dose maintained during the 
Maintenance Period. For subjects taking the LCM oral solution, weekly decrements of
either 2mg/kg/day or 3mg/kg/day (based on body weight) are recommended during the 
Taper Period. For subjects taking the LCM tablets, a weekly decrement of 200mg/day per 
week during the Taper Period is recommended. 
Table 7-2, Table 7-3 and Table 7-4 display the recommended LCM dose reductions during 
the Taper Period for the LCM oral solution and tablet formulations, respectively.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 99 of 203
Table 7-2
Recommended LCM dose taper for oral solution formulation for 
subjects weighing ≤30kg
Maximum LCM dose 
maintained
Taper schedule
Week 17
Week 18
Week 19
Week 20
12mg/kg/day
9mg/kg/day
6mg/kg/day
3mg/kg/day
0
9mg/kg/day
6mg/kg/day
3mg/kg/day
0
-
6mg/kg/day
3mg/kg/day
0
-
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3mg/kg/day
0
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LCM=lacosamide
Table 7-3
Recommended LCM dose taper for oral solution formulation for 
subjects weighing >30kg to ≤50kg
Maximum LCM dose 
maintained
Taper schedule
Week 17
Week 18
Week 19
Week 20
8mg/kg/day
6mg/kg/day
4mg/kg/day
2mg/kg/day
0
6mg/kg/day
4mg/kg/day
2mg/kg/day
0
-
4mg/kg/day
2mg/kg/day
0
-
-
2mg/kg/day
0
-
-
-
LCM=lacosamide
Table 7-4
Recommended LCM dose taper for tablet formulation for subjects 
weighing >50kg
Maximum LCM dose 
maintained
Taper schedule
Week 17
Week 18
400mg/day
200mg/day
0
300mg/day
100mg/day
0
200mg/day
0
-
100mg/day
0
-
LCM=lacosamide
All subjects discontinuing treatment with LCM for any reason should taper off LCM. It is 
recommended that the dosage be tapered off in weekly decrements of either 2mg/kg/day or 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 100 of 203
3mg/kg/day (based on body weight; oral solution) or 200mg/day (tablet). A slower taper is 
permitted if medically necessary. Whenever possible, these cases should be discussed with 
the medical monitor prior to withdrawing the subject from the study, especially in cases in 
which exit criteria have been met. In case of an emergency, a faster taper is permitted after 
discussion with the medical monitor, whenever possible.
If subjects discontinue prematurely from the study, an Early Termination Visit will occur
where subjects will be instructed to taper their LCM dose as appropriate. Subjects who do 
not complete the full 12 weeks of the Maintenance Period may still be eligible to enter 
the SP848 open-label study after consultation with the medical monitor.
Change #20
Section 7.3 packaging
Lacosamide tablets will be packaged in high-density polyethylene bottles with a child-proof 
polypropylene screw cap. The oral solution (syrup) will be packaged in amber polyethylene 
terephthalate bottles with a white, child-proof, polypropylene screw cap.
Has been changed to:
Lacosamide tablets will be packaged in high-density polyethylene bottles with a child-proof 
polypropylene screw cap. The oral solution will be packaged in amber polyethylene 
terephthalate bottles with a white, child-proof, polypropylene screw cap.
Change #21
Section 7.8.1 Permitted concomitant treatments (medication and therapies)
Benzodiazepines are allowed as 1 of 3 stable concomitant AEDs for treatment of epilepsy. 
See Section 7.8.3 for use of benzodiazepines as rescue medication.
Section 7.8.2 (Prohibited concomitant treatments (medication and therapies)
The following concomitant medications are prohibited during the study:
•
MAO inhibitors
•
Narcotic analgesics
All concomitant medications and treatments must be recorded in the appropriate study
documents (eCRF and source document) and doses should remain stable during the study.
The use of MAO inhibitors and narcotic analgesics is prohibited throughout the study. Only 
stable use of amphetamines and sedative antihistamines is allowed during the study. Also, 
only stable, low doses of anxiolytics or hypnotics (ie, diazepam 5mg/day) are allowed for 
nonepilepsy indications.
Therapy that becomes necessary, in the investigator’s opinion, during the course of the study 
must not be refused to a subject, even if described above as a therapy that is expressly not 
permitted. The subject’s participation in this study may be discontinued in such a case.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 101 of 203
Section 7.8.3 Rescue medication
The use of rescue medication (including benzodiazepines as rescue therapy for epilepsy) is 
allowed if taken at a maximum frequency of 1 day per month, where 1 month is defined as 
28 days. Intermittent use of benzodiazepines for any other indication is prohibited during the 
study. If rescue medication use or the most recent seizure is within 24 hours of assessments, 
the seizure/rescue medication date relative to assessments should be documented.
Have been changed to:
Section 7.8.1 Permitted and prohibited concomitant treatments (medications and 
therapies)
Subject must have been maintained on a stable dose regimen of up to 3 marketed AEDs 
for at least 4 weeks prior to Visit 1 (ie, prior to entry into the Baseline Period).
Vagal nerve stimulation is allowed and will not be counted as a concomitant AED. 
Vagal nerve stimulation (implanted for at least 6 months and stable for at least 4 weeks 
before Visit 1) must be kept stable during the Baseline Period and the Maintenance 
Period.
The following medications/therapies are prohibited during the course of this study:
•
Neuroleptics
•
Monoamine oxidase (MAO) inhibitors
•
Barbiturates (except as anti-epileptic medications)
•
Narcotic analgesics
Only stable use of amphetamines and sedative antihistamines is allowed during the 
study. Only stable, low doses of anxiolytics or once-daily hypnotics are allowed for non 
epilepsy indications.
Subjects who have been treated with vigabatrin and experienced any vision loss are 
excluded from the study. Subjects who have received vigabatrin in the past must have 
documentation of an assessment for vision loss prior to study entry or documentation of 
why visual field testing cannot be performed.
Subjects who have been treated with felbamate and have experienced any serious 
toxicity issues (defined as liver failure, aplastic anemia) with this treatment are excluded 
from the study. Subjects treated with felbamate for less than 12 months are also 
excluded. Any subject who has been treated with felbamate for at least 12 months and 
has not experienced serious toxicity issues is eligible for the study.
The chronic use of benzodiazepines is allowed for treatment of epilepsy. 
Benzodiazepines taken for treatment of epilepsy will be counted as 1 of the AEDs and 
the dose regimen must be stable for at least 28 days prior to Visit 1. Intermittent use of 
benzodiazepines as rescue therapy for epilepsy is allowed if taken at a maximum 
frequency of 1 day per month (with up to 3 doses within 24 hours). 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 102 of 203
Oral contraceptive use is allowed if ethinylestradiol dosage is at least 30μg per intake 
(50μg if associated with carbamazepine or other strong enzyme inducers [eg, 
phenobarbital, primidone, oxcarbazepine]).
Therapy that becomes necessary (in the investigator’s opinion) during the course of the 
study must not be refused to a subject, even if described above as a therapy that is 
expressly not permitted. In cases where this occurs but withdrawal criteria have not 
been met, the advisability of the subject’s continuation in the study must be discussed 
between the medical monitor and the investigator.
Section 7.8.2 Rescue medication
The use of benzodiazepines as rescue therapy for epilepsy is allowed if taken at a 
maximum frequency of 1 day per month (with up to 3 doses within 24 hours) during 
study participation; more frequent use precludes subjects from study participation.
Change #22
Section 8.1.1 Visit 1 (Week -6) Screening Visit
The following assessments have been modified/added:
•
Changes in VNS settings.
•
Vital signs (BP and pulse, including orthostatic assessments).
•
Epilepsy surgery assessment.
•
Health care resource use.
The following assessments have been deleted:
•
Achenbach CBCL (if applicable); CBCL/1½-5 or CBCL/6-18 for pediatric subjects
≥18 months of age.
•
Bayley Scales of Infant and Toddler Development®, Third Edition (Bayley-III Scales) (if 
applicable). For pediatric subjects <18 months of age at Baseline enrolled in 
English-speaking countries.
Change #23
Section 8.1.3 Visit 2 (Week 0)
The following assessments have been modified/added:
•
Review inclusion/exclusion criteria.
•
Changes in VNS settings.
•
Vital signs (BP and pulse, including orthostatic assessments).
•
Achenbach CBCL (if applicable); CBCL/1½-5 or CBCL/6-18 for pediatric subjects 
≥18 months of age.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 103 of 203
•
Bayley Scales of Infant and Toddler Development®, Third Edition (Bayley-III
Scales) (if applicable). For pediatric subjects <18 months of age at Baseline enrolled 
in English-speaking countries. 
•
BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) (version consistent 
with age at the visit).
•
PedsQL for subjects ≥1 month to ≤18 years of age (version consistent with age at the 
visit).
•
Health care resource use.
•
Dispense LCM. Subjects should take the first dose of LCM based on body weight in the 
clinic. The starting dose for subjects taking the oral solution formulation will be either 
2mg/kg/day or 3mg/kg/day, and the starting dose for subjects taking the tablet 
formulation will be 100mg/day.
Change #24
Section 8.2.1 Visit 3 (Week 1)
The following assessments have been modified/added:
•
Changes in VNS settings.
•
Vital signs (BP and pulse, including orthostatic assessments).
•
Body weight assessment.
•
Health care resource use.
•
Dispense LCM. The subject’s LCM dose can be titrated based on body weight to either 
4mg/kg/day or 6mg/kg/day (oral solution) or 200mg/day (tablets), if clinically 
appropriate.
Change #25
Section 8.2.2 Visit 4 (Week 2)
The subject’s dose can be titrated to LCM 9mg/kg/day (syrup) or 300mg/day (tablets), if 
clinically appropriate.
Has been changed to:
The subject’s LCM dose can be titrated based on body weight to either 6mg/kg/day or 
9mg/kg/day (oral solution) or 300mg/day (tablets), if clinically appropriate.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 104 of 203
Change #26
Section 8.2.3 Visit 5 (Week 3)
The subject’s dose can be titrated to LCM 12mg/kg/day (syrup) or 400mg/day (tablets), if 
clinically appropriate.
Has been changed to:
The subject’s LCM dose can be titrated based on body weight to either 8mg/kg/day or 
12mg/kg/day (oral solution) or 400mg/day (tablets), if clinically appropriate.
Change #27
Section 8.2.4 Visit 6 (Week 4)
The following assessments have been modified/added:
•
Changes in VNS settings.
•
Vital signs (BP and pulse, including orthostatic assessments).
•
Body weight assessment.
•
Achenbach CBCL (if applicable); CBCL/1½-5 or CBCL/6-18 for pediatric subjects 
≥18 months of age.
•
Health care resource use.
Change #28
Section 8.3.1 Telephone contacts (Weeks 6, 10 and 14)
The following text has been added:
Subjects must titrate to at least 6mg/kg/day for subjects weighing ≤30kg, 4mg/kg/day 
for subjects weighing >30kg to ≤50kg, or 200mg/day (tablets/oral solution) for subjects 
weighing >50kg in order to enter the Maintenance Period.
Change #29
Section 8.3.2 Visit 7 (Week 8)
The following assessments have been modified/added:
•
Changes in VNS settings.
•
Vital signs (BP and pulse, including orthostatic assessments).
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 105 of 203
•
Body weight assessment.
•
Health care resource use.
Change #30
Section 8.3.4 Visit 9 (Week 16)/Early Termination Visit
The following assessments have been modified/added:
•
Changes in VNS settings.
•
Vital signs (BP and pulse, including orthostatic assessments).
•
Urine sample for urinalysis (if applicable).
•
BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) (version consistent 
with age at Visit 2).
•
PedsQL for subjects ≥1 month to ≤18 years of age (version consistent with age at 
Visit 2).
•
Dispense subject diary (for subjects entering Taper Period and not SP848).
•
Health care resource use.
•
Dispense LCM (for subjects entering Taper Period and not SP848).
Subjects may be eligible for participation in the open-label study (SP848) if they have been 
maintained on a dose of at least 6mg/kg/day (syrup) or 200mg/day (tablets) LCM in the 
Maintenance Period. Subjects will begin SP848 on the LCM dose they were taking in the 
Maintenance Period in SP0966.
Subjects who choose not to participate in the open-label study, subjects who are not able to 
tolerate the lowest LCM dose (100mg/day for the tablet formulation or 3mg/kg/day for the 
syrup formulation), or subjects discontinuing due to other reasons will enter up to a 4-week 
Taper Period followed by a 1-week study drug-free Safety Period and Final Safety telephone 
contact.
Has been changed to:
Subjects may be eligible for participation in the open-label study (SP848) if they have been 
maintained on a dose of at least 6mg/kg/day (oral solution) for subjects weighing ≤30kg, 
4mg/kg/day (oral solution) for subjects weighing >30kg to ≤50kg, and 
200mg/day (tablets/oral solution) in subjects weighing >50kg in the Maintenance Period. 
Subjects will begin SP848 on the LCM dose they were taking in the Maintenance Period in 
SP0966.
Subjects who choose not to participate in the open-label study, subjects who are only able to 
tolerate the lowest LCM dose (100mg/day for the tablet formulation, 3mg/kg/day or 
2mg/kg/day for the oral solution formulation), or subjects discontinuing due to other 
reasons will enter up to a 4-week Taper Period followed by a 1-week study drug-free Safety 
Period and Final Safety telephone contact.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 106 of 203
Change #31
Section 8.4.1 Taper Period (Weeks 17 to 20)/End of Taper Visit
The following assessments have been modified/added:
•
Changes in VNS settings.
•
Vital signs (BP and pulse, including orthostatic assessments).
•
Body weight assessment.
•
Health care resource use.
Change #32
Section 8.5 Unscheduled Visit
The following assessments have been modified/added:
•
Changes in VNS settings
•
Vital signs (BP and pulse, including orthostatic assessments)
•
Health care resource use
The following text has been added:
In addition to the required assessments listed above, further assessments can be completed as 
needed and may include ECG, laboratory tests, physical examination, neurological 
examination, etc.
Change #33
Section 9 ASSESSMENT OF EFFICACY
The following sections have been added:
Section 9.3 Pediatric Quality of Life Inventory
The PedsQL is a validated instrument that consists of generic core scales suitable for 
use with pediatric populations, including those with acute or chronic health conditions 
(Varni et al, 2001; Varni et al, 2011). The PedsQL will be administered at Visit 2 and at 
Visit 9/Early Termination. For the Visit 9/Early Termination assessment, subjects will 
complete the version consistent with their age at Visit 2.
The PedsQL Measurement Model consists of developmentally appropriate forms for 
pediatric subjects ≥1 month to ≤12 months; ≥13 months to ≤24 months; >2 years to 
≤4 years, ≥5 years to ≤7 years, ≥8 years to ≤12 years, and ≥13 years to ≤18 years of age. 
Self-report is measured for pediatric subjects ≥5 years to ≤18 years of age, and parent 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 107 of 203
proxy report of child health-related quality of life (HRQoL) is measured for pediatric 
subjects ≥1 month to ≤18 years of age. 
The multidimensional PedsQL scale encompasses the essential core domains for 
pediatric HRQoL measurement: 1) Physical Functioning/Symptoms, 2) Emotional 
Functioning, 3) Social Functioning, and 4) Cognitive/School Functioning. The PedsQL 
assessment is retrospective to the prior month, and individual items are scored using a 
5-point Likert scale (never, almost never, sometimes, often, or always). A total health 
summary score is calculated from the sum of the raw scores of the individual items, with 
higher scores indicating higher HRQoL.
Section 9.4 Health care resource use
For health care resource use parameters, the following will be evaluated: concomitant 
AEDs, medical procedures, health care provider consultations not related to study, 
hospitalizations not related to study. Health care resource use parameters will be 
collected according to the tabular schedule of study procedures, Section 5.2.
Change #34
Section 11.3 Adverse events 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 
(<45 beats/min)
Has been changed to:
•
The following arrhythmias: atrial fibrillation/flutter, ventricular tachycardia or fibrillation, 
AV block (second degree, Type I and II, and third degree), and marked bradycardia for 
subject’s age 
Change #35
Section 11.7.4 Vital signs, body weight and height
Noninvasive BP (systolic and diastolic) and pulse will be measured at clinic visits in a sitting 
position after at least 3 minutes at rest, according to the tabular schedule of study procedures 
in Section 5.2. Body weight will be determined without shoes and wearing light clothing, and 
height will be measured without shoes. Body weight and height will be assessed according to 
the tabular schedule of study procedures in Section 5.2.
Has been changed to:
Noninvasive BP (systolic and diastolic) and pulse rate will be measured at clinic visits after 
at least 3 minutes at rest in a supine position, according to the tabular schedule of study 
procedures (Section 5.2). Assessment of orthostatic changes (only in ambulatory 
subjects) will be as follows: after the 3-minute measurement in supine position, the 
subject is asked to stand up, and BP and pulse rate are taken at approximately 1 minute 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 108 of 203
and 3 minutes after standing up, as feasible. Body weight will be determined without shoes 
and wearing light clothing, and height will be measured without shoes. Body weight and 
height will be assessed according to the tabular schedule of study procedures in Section 5.2.
Change #36
Section 11.7.8 Achenbach CBCL
The same scale will be completed at Visit 1, Visit 9 (or the Early Termination Visit) and 
again by the same parent(s) or legal representative(s) in the open-label study, SP848 (if 
applicable). The completion of the Achenbach CBCL will require approximately 45 minutes. 
Has been changed to:
The same scale will be completed at Visit 2, Visit 6, and Visit 9 (or the Early Termination 
Visit) and again by the same parent(s) or legal representative(s) in the open-label study, 
SP848 (if applicable). The completion of the Achenbach CBCL will require approximately 
45 minutes.
Change #37
Section 11.7.9 Bayley Scales of Infant and Toddler Development, Third Edition
The same scale will be completed at Visit 1 and again in the open-label study, SP848 (if 
applicable).
Has been changed to:
The same scale will be completed at Visit 2 and again in the open-label study, SP848 (if 
applicable).
Change #38
The following section has been added:
Section 11.7.10 Behavior Rating Inventory of Executive Function
The BRIEF-P and the BRIEF are validated tools that will be used for the evaluation of 
subjects ≥2 years to <5 years of age and ≥5 years of age, respectively. The 
BRIEF-P/BRIEF will be administered at Visit 2 and at Visit 9/Early Termination. For 
the Visit 9/Early Termination assessment, subjects will complete the version consistent 
with their age at Visit 2.
The BRIEF-P and BRIEF include rating forms used by parents to assess subjects’ 
executive functioning. Executive functions broadly encompass a set of cognitive skills 
that are responsible for the planning, initiation, sequencing, and monitoring of complex 
goal-directed behavior.
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 109 of 203
The BRIEF-P rating form consists of items that measure various aspects of executive 
functioning: Inhibit, Shift, Emotional Control, Working Memory, and Plan/Organize. 
The clinical scales form 3 broad indexes (Inhibitory Self-Control, Flexibility, and 
Emergent Metacognition) and 1 composite score (Global Executive Composite).
The BRIEF rating form contains items in nonoverlapping clinical scales. These
theoretically and statistically derived scales form 2 broader Indexes: Behavioral 
Regulation (3 scales) and Metacognition (5 scales), as well as a Global Executive 
Composite score.
Both the BRIEF-P and the BRIEF include validity scales to measure negativity and 
inconsistency of responses.
Change #39
Section 11.7.11 Assessment of suicidality
The following text has been added:
The “Since Last Visit” version of the C-SSRS will be used, with the following 
exceptions:
•
The “Baseline/Screening” version of the C-SSRS should be completed at Visit 1. 
•
If a subject turns 6 years of age during the study, the “Already Enrolled” version of 
the C-SSRS should be completed at the first visit after the sixth birthday.
Change #40
Section 13.3.3 Other safety analyses
Other variables assessing safety are: ECG, measurements of laboratory parameters 
(hematology, clinical chemistry, urinalysis, and hormone status) and vital signs (including 
body weight, height and BMI), physical and neurological examination findings, and 
assessments of Tanner stage (if applicable), and Achenbach CBCL.
Has been changed to:
Other variables assessing safety are: ECG, measurements of laboratory parameters 
(hematology, clinical chemistry, urinalysis, and hormone status) and vital signs (including 
body weight, height and BMI), physical and neurological examination findings, assessments 
of Tanner stage (if applicable), Achenbach CBCL, and BRIEF-P/BRIEF.
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 110 of 203
Change #41
Section 13.4.1 Preliminary efficacy analyses
Descriptive statistics to summarize the percent change in seizure days per 28 days from 
Baseline Period to the Maintenance Period will be presented for any generalized seizures 
reported and for each generalized seizure type.
Descriptive summaries will also be presented for the Clinical and Caregiver’s Global 
Impression of Change.
Has been changed to:
Descriptive statistics to summarize the absolute and percent change in seizure days per 28 
days from Baseline Period to the Maintenance Period will be presented for any generalized
seizures reported and for each generalized seizure type.
Descriptive summaries will also be presented for the Clinical and Caregiver’s Global 
Impression of Change, health care resource use, and the PedsQL.
Change #42
Section 13.6 Handling of drop outs or missing data
•
Subjects discontinued prematurely during the Titration Period: estimates will be 
calculated using all available data in the Titration Period and carried forward for the 
Maintenance
Has been changed to:
•
Subjects discontinued prematurely during the Titration Period: estimates will be 
calculated using all available data in the Titration Period and carried forward for the 
Maintenance Period.
Change #43
Section 16 References
The following references have been added:
Varni JW, Limbers CA, Neighbors K, Schulz K, Lieu JE, Heffer RW, et al. The 
PedsQL™ Infant Scales: feasibility, internal consistency reliability, and validity in 
healthy and ill infants. Qual Life Res. 2011;20:45-55.
Varni JW, Seid M, Kurtin PS. PedsQL 4.0: reliability and validity of the Pediatric 
Quality of Life Inventory version 4.0 generic core scales in healthy and patient 
populations. Med Care. 2001;39:800-12. 
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 111 of 203
17.3
Protocol Amendment 2
Rationale for the amendment
This nonsubstantial Amendment has been issued in order to correct a typographical error in 
the protocol. An LCM dose of 400mg/kg/day was stated in the protocol, but the correct dose 
is 400mg/day. 
In addition, a requirement to practice 2 combined methods of contraception was added to the 
protocol (for consistency with SP0969), and wording pertaining to suicide attempts and 
suicidal ideation captured by the C-SSRS was updated, in order to ensure the protocol is 
consistent with this global change for all UCB protocols. Furthermore, more detail was added 
as guidance to the investigator regarding the proper storage of the IMP (LCM) at the site.
Modifications and changes
Specific changes
Change #1
Section 5.1 Study description
If a subject does not achieve or require the maximum dose level (8mg/kg/day, 12mg/kg/day,
or 400mg/kg/day), then the highest optimized dose will be maintained until the end of the 
Titration Period.
Has been changed to:
If a subject does not achieve or require the maximum dose level (8mg/kg/day, 12mg/kg/day,
or 400mg/day), then the highest optimized dose will be maintained until the end of the 
Titration Period.
Change #2
Section 6.2 Exclusion criteria
Exclusion criterion number 8
Subject has a lifetime history of suicide attempt (including an active attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the Columbia Suicide
Severity Rating Scale (C-SSRS) at Screening.
Has been changed to:
Exclusion criterion number 8
Subject has a lifetime history of suicide attempt (including an actual attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the Columbia Suicide 
Severity Rating Scale (C-SSRS) at Screening.
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 112 of 203
Exclusion criterion number 21
Subject is a female of childbearing potential or the subject achieves menarche during the 
study and does not practice an acceptable method of contraception for the duration of the 
study. 
−
Medically acceptable contraceptive method includes oral or depot contraceptive 
treatment with at least 30μg ethinylestradiol per intake (or 50μg if associated with 
carbamazepine [or other strong enzyme inducers, eg, phenobarbital, primidone, 
oxcarbazepine]) which must be used in conjunction with a barrier method. Sexual 
abstinence is also an acceptable method of contraception.
−
The subject must understand the consequences and potential risks of inadequately 
protected sexual activity, be educated about and understand the proper use of 
contraceptive methods, and undertake to inform the investigator of any potential 
change in status. Females of childbearing potential must have a negative pregnancy 
test at the Screening Visit (Visit 1).
Has been changed to:
Exclusion criterion number 21
Subject is a female who is pregnant or nursing, and/or a female of childbearing potential 
(or who achieves menarche during the study) who does not practice 2 combined 
methods of contraception, unless sexually abstinent, for the duration of the study. Male 
subject who does not agree to practice 2 combined methods of contraception 
(eg, condom, spermicide), unless sexually abstinent, for the duration of the study.
−
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treatment with at least 30μg ethinylestradiol per intake (or 50μg if associated with 
carbamazepine [or other strong enzyme inducers, eg, phenobarbital, primidone, 
oxcarbazepine]), which must be used in conjunction with a barrier method. Sexual 
abstinence is also an acceptable method of contraception.
−
The subject must understand the consequences and potential risks of inadequately 
protected sexual activity, be educated about and understand the proper use of 
contraceptive methods, and undertake to inform the investigator of any potential 
change in status. Females of childbearing potential must have a negative pregnancy 
test at the Screening Visit (Visit 1).
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 113 of 203
Change #3
Section 6.3 Withdrawal criteria
Withdrawal criterion number 12
Subject has active suicidal ideation as indicated by a positive response (“Yes”) to either 
Question 4 or Question 5 of the “Since Last Visit” version of the C-SSRS. The subject should 
be referred immediately to a Mental Healthcare Professional and must be withdrawn from the
study.
Has been changed to:
Withdrawal criterion number 12
Subject has actual suicidal ideation as indicated by a positive response (“Yes”) to either 
Question 4 or Question 5 of the “Since Last Visit” version of the C-SSRS. The subject should 
be referred immediately to a Mental Healthcare Professional and must be withdrawn from the 
study.
Change #4
Section 7.2 Treatments(s) to be administered
If a subject does not achieve or require the maximum dose level (8mg/kg/day, 12mg/kg/day, 
or 400mg/kg/day), then the highest optimized dose will be maintained until the end of the 
Titration Period.
Has been changed to:
If a subject does not achieve or require the maximum dose level (8mg/kg/day, 12mg/kg/day,
or 400mg/day), then the highest optimized dose will be maintained until the end of the 
Titration Period.
Change #5
Section 7.5 Handling and storage requirements
Lacosamide is to be stored according to the instructions on the label.
Has been changed to:
Lacosamide is to be stored according to the instructions on the label. Lacosamide is stable at 
room temperature and is to be stored at temperatures not exceeding 25°C (77°F). 
Lacosamide should not be frozen.
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 114 of 203
17.4
Protocol Amendment 3
Rationale for the amendment
The present amendment has been issued following additional feedback from the USA FDA 
on both SP0969 and SP0966. Where applicable, the recommendations made by the FDA have 
been incorporated into the current protocol. In addition, updates were made for consistency 
with other LCM protocols. The following major changes were made:
•
The titration and taper schedules were changed to include different weight categories, a
600mg/day LCM dose, and an extended (slower) titration schedule.
•
The schedule of assessments was modified to include the changes to the titration 
schedule, additional visits, and changes to the assessments at each visit.
•
The schematic diagrams were updated to reflect the additional changes to the titration and 
taper schedules.
•
Inclusion criteria were modified to allow inclusion of subjects with West syndrome.
•
Measurements of head circumference were included.
•
The language regarding unscheduled visits was updated to make it clear that investigators 
can perform additional procedures based on their judgment and medical need.
•
The age allowed for initial enrollment was reduced from 4 to 2 years.
•
The duration of the safety follow-up was made consistent with other LCM studies
(SP0969).
•
The definition of end of study for the subjects has been clarified to account for subjects 
who enter and do not enter the open-label study.
•
Additional language was added describing the procedures if the study is completed and 
the taper is not required at the end of the study.
•
The language regarding study medication storage has been updated according to the 
clinical label.
•
The language regarding some of the scales used in this study has been updated for 
clarification. 
•
The number of sites and countries in the study were increased.
•
Administrative changes were made; the Clinical Project Manager details were updated-.
•
Typographical changes were made to improve clarity of wording and to reflect the 
contents of other LCM studies (SP0969).
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 115 of 203
Modifications and changes
Global changes
The following key changes were made throughout the protocol:
•
Dosing was changed: SP0966 will explore doses of LCM at 4 to 12mg/kg/day in children 
<50kg and LCM 200 to 600mg/day for subjects weighing ≥50kg.
•
Flexible titration was introduced to allow back-titration if subjects can not tolerate higher 
doses of LCM.
•
The taper schedule was modified.
•
Numbers for Visit and Week were updated as needed.
•
Text was changed throughout the protocol to match other LCM studies (SP0969) and to 
reflect changes to the schedule of assessments and visits.
Specific changes
Change #1
SPONSOR DECLARATION
Clinical Project Manager
, RN, MSN
Has been changed to:
Clinical Project Manager
, MD
Change #2
STUDY CONTACT INFORMATION
Clinical Project Manager 
Name:
, RN, MSN
Address:
UCB BIOSCIENCES Inc. 
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
Phone:
Fax:
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 116 of 203
Has been changed to:
Clinical Project Manager 
Name:
 MD
Address:
UCB BIOSCIENCES GmbH
Alfred-Nobel-Straße 10
40789 Monheim
GERMANY
Phone:
Fax:
Change #3
LIST OF ABBREVIATIONS
The following abbreviations were added to the protocol:
EI-AED
enzyme inducing antiepileptic drugs
QTc
corrected QT interval
The following abbreviation was deleted from the protocol:
CPM
Clinical Project Manager
Change #4
Section 1 SUMMARY, paragraphs 3, 4 and 5
Approximately 50 subjects will be enrolled in this study across approximately 40 sites in 
Europe, USA, and other regions as deemed necessary.
The study will begin with subject screening at Visit 1 and will consist of a 6-week 
prospective Baseline Period where seizure frequency will be captured through daily seizure 
diaries. At the end of the Baseline Period (completion of Visit 2), subjects will commence a 
4-week Titration Period, where subjects will initiate treatment with LCM. Subjects weighing 
≤30kg will begin treatment on LCM oral solution (syrup) 3mg/kg/day, subjects weighing 
>30kg to ≤50kg will begin treatment on LCM oral solution 2mg/kg/day, and subjects 
weighing >50kg will begin treatment on LCM tablets 100mg/day (subjects weighing >50kg 
who are unable or unwilling to swallow tablets can also be dispensed LCM oral solution). 
The dose will be titrated to a level to optimize tolerability and seizure control, not to exceed 
12mg/kg/day for subjects weighing ≤30kg, or 8mg/kg/day for subjects weighing >30kg to 
≤50kg, and 400mg/day (tablets/oral solution) in subjects weighing >50kg. At the end of the 
Titration Period (Visit 6), a 12-week Maintenance Period will begin. Subjects must titrate to 
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 117 of 203
at least 6mg/kg/day for subjects weighing ≤30kg, 4mg/kg/day for subjects weighing >30kg to 
≤50kg, or 200mg/day (tablets/oral solution) for subjects weighing >50kg in order to enter the 
Maintenance Period.
The end of the Maintenance Period will be Visit 9, or, if subjects withdraw early, the Early 
Termination Visit. Subjects may be eligible for participation in an additional open-label study 
(SP848) upon completion of the Maintenance Period and a minimum dose of 6mg/kg/day for 
subjects weighing ≤30kg, 4mg/kg/day for subjects weighing >30kg to ≤50kg, and 
200mg/day (tablets/oral solution) in subjects weighing >50kg. Subjects who do not complete 
the full 12 weeks of the Maintenance Period may still be eligible to enter the SP848 
open-label study after consultation with the medical monitor. Subjects who choose not to 
participate in the additional open-label study, subjects who are only able to tolerate the lowest 
LCM dose (100mg/day for the tablet formulation, 3mg/kg/day or 2mg/kg/day for the oral 
solution formulation), or subjects who are discontinuing due to other reasons will enter up to 
a 4-week Taper Period followed by a 1-week study drug-free Safety Period and Final Safety 
telephone contact. 
Have been changed to:
Approximately 50 subjects will be enrolled in this study across approximately 50 sites in 
Europe, Russia, and North America, and other regions as deemed necessary.
The study will begin with subject screening at Visit 1 and will consist of a 6-week 
prospective Baseline Period where seizure frequency will be captured through daily seizure 
diaries. At the end of the Baseline Period, subjects will commence a 6-week Titration Period
at Visit 2, where subjects will initiate treatment with LCM (LCM dosing flexibility allowed 
based on tolerability). Subjects weighing <50kg will begin treatment on LCM oral 
solution 2mg/kg/day, and subjects weighing ≥50kg will begin treatment on LCM tablets 
100mg/day (subjects weighing ≥50kg who are unable or unwilling to swallow tablets can be 
dispensed LCM oral solution instead). The dose will be titrated to a level to optimize 
tolerability and seizure control, not to exceed 12mg/kg/day (oral solution) for subjects 
weighing <50kg or 600mg/day (tablets/oral solution) for subjects weighing ≥50kg. At the 
end of the Titration Period (Visit 6), a 12-week Maintenance Period will begin. Subjects must 
titrate to at least 4mg/kg/day for subjects weighing <50kg or 200mg/day (tablets/oral 
solution) for subjects weighing ≥50kg in order to enter the Maintenance Period. The LCM 
dose will remain stable throughout the Maintenance Period. Subjects who require a 
change in dose during the Maintenance Period will be withdrawn from the study.
Subjects who require a change in formulation during the Maintenance Period should 
consult the medical monitor to assess if the subject can continue in the study.
The end of the Maintenance Period will be Visit 9, or, if subjects withdraw early, the Early 
Termination Visit. Subjects may be eligible for participation in an additional open-label study 
(SP848) if they have completed the Maintenance Period and are taking a minimum dose of 
4mg/kg/day for subjects weighing <50kg or 200mg/day (tablets/oral solution) for
subjects weighing ≥50kg. Subjects who do not complete the full 12 weeks of the 
Maintenance Period may still be eligible to enter the SP848 open-label study after 
consultation with the medical monitor. Subjects who choose not to participate in the 
additional open-label study or subjects who discontinue LCM due to other reasons will enter 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 118 of 203
a 2- to 4-week Taper Period followed by a Safety Follow-Up Visit 2 weeks (±2 days) 
after the final dose of LCM and a Safety Follow-Up Telephone Contact 30 days 
(-1/+3 days) after the final dose of LCM. Taper of LCM may not be required for some 
subjects who discontinue study medication prematurely, depending on the treatment 
option selected by the investigator in consultation with the subject and/or parent/legal 
representative.
Change #5
Section 2 INTRODUCTION, paragraphs 1, 4, 5, 8, 11, and 13
Epilepsy is the second most prevalent neurological disorder in the world. More than 
40 million people suffer from epilepsy–about 1% of the world’s population (Dichek, 1999). 
Although some forms of epilepsy may respond to surgical treatment and others may not 
require any treatment at all, most patients with epilepsy require appropriate pharmacological 
therapy (Perucca, 1996). In the past decade, several new options for the medical treatment of 
epilepsy have been introduced, including novel AEDs and vagus nerve stimulation (VNS).
Among the newer AEDs, only 5 (gabapentin, lamotrigine, oxcarbazepine, topiramate, and 
levetiracetam) have successfully demonstrated efficacy as adjunctive therapy in pediatric 
subjects with difficult to treat partial-onset seizures (Glauser et al, 2006; Glauser et al, 2000; 
Appleton et al, 1999; Duchowny et al, 1999; Elterman et al, 1999). Despite the availability of 
new AEDs, >25% of pediatric patients have inadequate seizure control on currently available 
AEDs or experience significant adverse drug effects (Hadjiloizou and Bourgeois, 2007).
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, 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’s 
mode of action is proposed to be mediated by a selective enhancement of slow inactivation of 
voltage-gated sodium channels which may explain the immediate analgesic and 
anticonvulsant effects of LCM (Errington et al, 2008).
In the clinical development program for LCM, safety and tolerability of multiple doses of up 
to 400mg bid (800mg/day) were evaluated in approximately 856 unique volunteers who 
received LCM in Phase 1 studies. The safety and efficacy of LCM has also been evaluated in 
Phase 2/3 studies as adjunctive oral therapy in over 1300 adult subjects with partial-onset 
seizures and as oral monotherapy in over 2200 adult subjects in other indications (eg, 
neuropathic pain, osteoarthritis, fibromyalgia, and migraine prophylaxis). In addition, LCM 
solution for infusion was evaluated as short-term replacement therapy in a subset of subjects 
with partial-onset seizures (199 patients) who were receiving adjunctive LCM tablets.
UCB has completed a Phase 2, open-label safety study (SP0961) of adjunctive LCM 
treatment for primary generalized tonic-clonic seizures in subjects ≥ 16 years of age with 
idiopathic generalized epilepsy. The results of SP0961 showed reductions in primary 
generalized tonic-clonic seizure frequency and myoclonic seizure days, with a small 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 119 of 203
reduction in absence seizure days. A minority of subjects (~10%) showed an increase in 
absence seizures (reported as TEAEs) that, in this uncontrolled study, cannot be distinguished 
between the drug versus the natural course of the disease. The AE profile was similar to that 
of adjunctive LCM for the treatment of subjects with partial-onset seizures, with the 
exception of seizure-related AEs.
SP0966 is a Phase 2, multicenter, open-label exploratory study designed to assess the safety 
and preliminary efficacy of oral LCM as adjunctive therapy for epilepsy syndromes 
associated with generalized (Type II) seizures in pediatric subjects ≥1 month to <18 years of 
age. Initially, only subjects ≥4 years of age will be included in this study. Once the LCM dose 
range has been defined in subjects <4 years of age, enrollment of subjects in the younger 
cohort will begin.
Have been changed to:
Epilepsy is the second most prevalent neurological disorder in the world. More than 
40 million people suffer from epilepsy–about 1% of the world’s population (Dichek, 1999). 
Although some forms of epilepsy may respond to surgical treatment and others may not 
require any treatment at all, most patients with epilepsy require appropriate pharmacological 
therapy (Perucca, 1996). The Institute of Medicine of the National Academies recently 
provided a review of the burdens of epilepsy, global incidence and prevalence of 
epilepsy, classification systems for seizure types and syndromes, gaps in information 
about epilepsy, and general recommendations (Institute of Medicine, 2012). Several new 
options for the medical treatment of epilepsy have been introduced, including novel AEDs
and vagus nerve stimulation (VNS).
Among the newer AEDs, only 6 (gabapentin, lamotrigine, oxcarbazepine, topiramate, 
levetiracetam, and perampanel) have successfully demonstrated efficacy as adjunctive 
therapy in pediatric subjects with difficult to treat partial-onset seizures (Appleton et al, 1999; 
Duchowny et al, 1999; Elterman et al, 1999; Glauser et al, 2000; Glauser et al, 2006; 
Rheims and Ryvlin, 2013). Despite the availability of new AEDs, more than 25% of 
pediatric patients have inadequate seizure control on currently available AEDs or experience 
significant adverse drug effects (Hadjiloizou and Bourgeois, 2007).
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, 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’s 
mode of action is proposed to be mediated by a selective enhancement of slow inactivation of 
voltage-gated sodium channels which may explain the immediate anticonvulsant effects of 
LCM (Errington et al, 2008).
In the clinical development program for LCM, safety and tolerability of multiple doses of up 
to LCM 400mg bid (800mg/day) were evaluated in 868 unique subjects who received oral 
and/or iv LCM in Phase 1 studies. The safety and efficacy of LCM has also been evaluated 
in Phase 2/3 studies as adjunctive oral therapy in 1427 adult subjects with partial-onset 
seizures, as oral monotherapy in 425 adult subjects with partial-onset seizures, as 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 120 of 203
adjunctive oral therapy in 49 subjects with primary generalized tonic-clonic seizures,
and as oral monotherapy in 2435 adult subjects in other indications (eg, neuropathic pain, 
osteoarthritis, fibromyalgia, and migraine prophylaxis). In addition, LCM solution for 
infusion was evaluated as short-term replacement therapy in a subset of subjects with 
partial-onset seizures (199 patients) who were receiving adjunctive LCM tablets.
UCB has completed a Phase 2, open-label safety study (SP0961) of adjunctive LCM 
treatment for primary generalized tonic-clonic seizures in 49 subjects ≥ 16 years of age with 
idiopathic generalized epilepsy. The results of SP0961 showed reductions in primary 
generalized tonic-clonic seizure frequency and myoclonic seizure days, with a small 
reduction in absence seizure days. A minority of subjects (~10%) showed an increase in 
absence seizures (reported as TEAEs) that, in this uncontrolled study, cannot be distinguished 
between the drug versus the natural course of the disease. The AE profile was similar to that 
of adjunctive LCM for the treatment of subjects with partial-onset seizures, with the 
exception of seizure-related AEs.
SP0966 is a Phase 2, multicenter, open-label exploratory study designed to assess the safety 
and preliminary efficacy of oral LCM as adjunctive therapy for epilepsy syndromes 
associated with generalized (Type II) seizures in pediatric subjects ≥1 month to <18 years of 
age. Initially, only subjects ≥2 years of age will be included in this study. Once the LCM dose 
range has been defined for subjects <2 years of age based on SP847, enrollment of subjects 
in this age group will begin in SP0966.
Change #6
Section 3 STUDY OBJECTIVES
The following objective has been added:
•
An additional objective is to evaluate the PK of LCM in subjects ≥1 month to <18 
years of age.
Change #7
Section 4.1.1 Primary safety variables
•
Changes in count of generalized spike-wave discharges on 24-hour ambulatory 
electroencephalogram (EEG) from Visit 2 (Baseline Period) to Visit 6 (start of 
Maintenance Period)
Has been changed to:
•
Changes in count of generalized spike-wave discharges on 24-hour ambulatory 
electroencephalogram (EEG) from Visit 2 to Visit 6 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 121 of 203
Change #8
Section 4.1.2 Secondary safety variables
•
Changes in count of 3Hz spike-wave discharges (during waking hours) on 24-hour 
ambulatory EEG from Visit 2 (Baseline Period) to Visit 6 (start of Maintenance Period)
Has been changed to:
•
Changes in count of 3Hz spike-wave discharges (during waking hours) on 24-hour 
ambulatory EEG from Visit 2 to Visit 6 
Change #9
Section 4.2 Preliminary efficacy variables
•
Changes in count of generalized spike-wave discharges on 24-hour ambulatory EEG from 
Visit 2 (Baseline Period) to Visit 9 (end of Maintenance Period) or at Early Termination
•
Changes in count of 3Hz spike-wave discharges (during waking hours) on 24-hour 
ambulatory EEG from Visit 2 (Baseline Period) to Visit 9 (end of Maintenance Period) or 
at Early Termination
Has been changed to:
•
Changes in count of generalized spike-wave discharges on 24-hour ambulatory EEG from 
Visit 2 to Visit 9 or at Early Termination
•
Changes in count of 3Hz spike-wave discharges (during waking hours) on 24-hour 
ambulatory EEG from Visit 2 to Visit 9 or at Early Termination
Change #10
Section 4.3 Pharmacokinetic variables
•
Plasma concentrations of LCM and concomitant AEDs
Has been changed to:
Section 4.3 Pharmacokinetic and pharmacodynamic variables
Plasma concentrations of LCM and concomitant AEDs will be obtained in order to: 
•
Develop a population PK model of LCM
•
Investigate the effect of LCM on the steady-state plasma concentrations of 
concomitant AEDs
•
Investigate the correlation between LCM plasma concentrations and efficacy or 
safety
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 122 of 203
Change #11
Section 5.1 Study description
SP0966 is a Phase 2, multicenter, open-label exploratory study designed to assess the safety 
and preliminary efficacy of oral LCM as adjunctive therapy for epilepsy syndromes 
associated with generalized seizures in pediatric subjects ≥1 month to <18 years of age.
Initially, only subjects ≥4 years of age will be included in this study. Once the LCM dose 
range has been defined in subjects <4 years of age, enrollment of subjects in the younger 
cohort will begin.
Subjects should have a current diagnosis of epilepsy with generalized seizures (Type II) 
according to the International Classification of Epileptic Seizures (1981), see Section 17.1.
The diagnosis should have been established by clinical history and an EEG with generalized 
spike-wave discharges. In addition to the Type II seizures, subjects with a current diagnosis 
of mixed seizure disorder(s), including both Type I and Type II seizures, are also eligible. 
Subjects with exclusively absence (Type IIA1) or atypical absence (Type IIA2) seizures are 
not eligible. Subjects with primary generalized tonic-clonic seizures with a diagnosis of 
idiopathic generalized epilepsy are also not eligible for this study as there is a confirmatory 
(Phase 3) study evaluating this seizure type.
The study treatment is LCM in either the oral solution formulation or tablet formulation. The 
formulation of LCM to be administered is based on the weight of the subject. Only subjects 
weighing >50kg who are able and willing to swallow tablets may be dispensed LCM tablets.
Subjects will not be randomized, but all subjects who sign the informed consent form (ICF) at 
Visit 1 will be assigned a unique identification number. 
The study will begin with subject screening at Visit 1 and will consist of a 6-week 
prospective Baseline Period where seizure frequency will be captured. Subjects/caregivers 
will maintain a diary to record daily seizure activity from Visit 1 until the end of the study. 
The subject diary will capture seizure type and seizure frequency information. If all inclusion 
criteria are met and no exclusion criteria are met, the subject will begin a 4-week Titration 
Period starting at Visit 2. Subjects will be asked to return to the clinic on the morning of the 
day prior to Visit 2 to begin 24-hour ambulatory EEG recordings. Subjects will initiate 
treatment with LCM oral solution at 2mg/kg/day or 3mg/kg/day, or LCM tablets at 
100mg/day based on body weight. The dose will be titrated to a level to optimize tolerability 
and seizure control, not to exceed 12mg/kg/day for subjects weighing ≤30kg, or 8mg/kg/day 
for subjects weighing >30kg to ≤50kg, and 400mg/day (tablets/oral solution) in subjects 
weighing >50kg. Subjects will increase the LCM dose in a stepwise fashion on a weekly 
basis to optimize tolerability and seizure control. During the Titration period only, one 
back-titration step is permitted; once the dose of LCM has been back-titrated, the dose cannot 
be increased for the duration of the study (see Figure 5-1 and Figure 5-2).
If a subject does not achieve or require the maximum dose level (8mg/kg/day, 12mg/kg/day, 
or 400mg/day), then the highest optimized dose will be maintained until the end of the 
Titration Period. The Titration Period will last 4 weeks, regardless of the doses administered. 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 123 of 203
Subjects who are not able to tolerate the minimum required dose (at least 6mg/kg/day for 
subjects weighing ≤30kg, 4mg/kg/day for subjects weighing >30kg to ≤50kg, or 
200mg/day [tablets/oral solution] for subjects weighting >50kg) of LCM (even after 
back-titration) will be withdrawn from the study. Study medication doses will be titrated 
according to the schedules presented in Table 7-1.
The maximum LCM dose is not to exceed 12mg/kg/day (oral solution) for subjects weighing 
≤30kg, 8mg/kg/day (oral solution) for subjects weighing >30kg to ≤50kg, and 
400mg/day (tablets/oral solution) in subjects weighing >50kg.
At the end of the Titration Period (Visit 6), a 12-week Maintenance Period will begin. 
Subjects must titrate to at least 6mg/kg/day for subjects weighing ≤30kg, 4mg/kg/day for 
subjects weighing >30kg to ≤50kg, or 200mg/day (tablets/oral solution) for subjects weighing 
>50kg in order to enter the Maintenance Period. Subjects will return to the clinic (on the 
morning of the day prior to the scheduled visit) at Visit 6 and Visit 9 or Early Termination for 
24-hour ambulatory EEG recordings for evaluation of spike-wave discharges. The end of the 
Maintenance Period will be Visit 9, or, if subjects withdraw early, the Early Termination 
Visit. Subjects may be eligible for participation in the additional open-label study (SP848) 
upon completion of the Maintenance Period and a minimum dose of 6mg/kg/day for subjects 
weighing ≤30kg, 4mg/kg/day for subjects weighing >30kg to ≤50kg, and 200mg/day 
(tablets/oral solution) in subjects weighing >50kg. Subjects who do not complete the full 
12 weeks of the Maintenance Period may still be eligible to enter the SP848 open-label study 
after consultation with the medical monitor. Subjects who choose not to participate in the 
open-label study, subjects who are only able to tolerate the lowest LCM dose (100mg/day for 
the tablet formulation, 3mg/kg/day or 2mg/kg/day for the oral solution formulation), or 
subjects who are discontinuing due to other reasons will enter up to a 4-week Taper Period 
followed by a 1-week study drug-free Safety Period and Final Safety telephone contact. 
Dosing schedules for the Taper Period are provided in Table 7-2, Table 7-3, and Table 7-4.
A Data Monitoring Committee (DMC) will oversee the safety of the study.
Has been changed to:
SP0966 is a Phase 2, multicenter, open-label exploratory study designed to assess the safety 
and preliminary efficacy of oral LCM as adjunctive therapy for epilepsy syndromes 
associated with generalized seizures in pediatric subjects ≥1 month to <18 years of age.
Initially, only subjects ≥2 years of age will be included in this study. Once the LCM dose 
range has been defined for subjects <2 years of age based on confirmation of supportive 
PK, safety, and tolerability dosing data from SP847, enrollment of subjects in this age 
group will begin in SP0966.
Subjects should have a current diagnosis of epilepsy with generalized seizures (Type II) 
according to the International Classification of Epileptic Seizures (1981), see Section 17.1. 
The diagnosis should have been established by clinical history and an EEG with generalized 
spike-wave discharges. In addition to the Type II seizures, subjects with a current diagnosis 
of mixed seizure disorder(s), including both Type I and Type II seizures, are also eligible. 
Subjects with exclusively absence (Type IIA1) or atypical absence (Type IIA2) seizures are 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 124 of 203
idiopathic generalized epilepsy are also not eligible for this study as there is a confirmatory 
(Phase 3) study evaluating this seizure type. 
The study treatment is LCM in either the oral solution formulation or tablet formulation. The 
formulation of LCM to be administered is based on the weight of the subject. Only subjects 
weighing ≥50kg who are able and willing to swallow tablets may be dispensed LCM tablets 
(subjects weighing ≥50kg who are unable or unwilling to swallow tablets can be 
dispensed LCM oral solution instead).
Subjects will not be randomized, but all subjects who sign the informed consent form (ICF) at 
Visit 1 will be assigned a unique identification number. 
The study will begin with subject screening at Visit 1 and will consist of a 6-week 
prospective Baseline Period where seizure frequency will be captured. Subjects/caregivers 
will maintain a diary to record daily seizure activity from Visit 1 until the end of the study. 
The subject diary will capture seizure type and seizure frequency information. If all inclusion 
criteria are met and no exclusion criterion is met, the subject will begin a 6-week Titration 
Period (LCM dosing flexibility allowed based on tolerability) starting at Visit 2. Subjects 
will be asked to return to the clinic on the morning of the day prior to Visit 2 to begin 24-hour 
ambulatory EEG recordings. Subjects will initiate treatment with LCM oral solution at 
2mg/kg/day, or LCM tablets at 100mg/day based on body weight. The dose will be 
titrated to a level to optimize tolerability and seizure control, not to exceed 12mg/kg/day 
(oral solution) for subjects weighing <50kg, or 600mg/day (tablets/oral solution) in 
subjects weighing ≥50kg. Subjects will increase the LCM dose in a stepwise fashion on a 
weekly basis to optimize tolerability and seizure control (see Figure 5-1 and Figure 5-2).
Lacosamide doses will be titrated according to the schedules presented in Table 7-1 and 
Table 7-2.
At the end of the Titration Period (Visit 6), a 12-week Maintenance Period will begin. The 
LCM dose will remain stable throughout the Maintenance Period. Subjects who require 
a change in dose during the Maintenance Period will be withdrawn from the study.
Subjects who require a change in formulation during the Maintenance Period should 
consult the medical monitor to assess if the subject can continue in the study.
Subjects must titrate to at least 4mg/kg/day for subjects weighing <50kg, or 
200mg/day (tablets/oral solution) for subjects weighing ≥50kg in order to enter the 
Maintenance Period. Subjects will return to the clinic (on the morning of the day prior to the 
scheduled visit) at Visit 6 and Visit 9 or Early Termination for 24-hour ambulatory EEG 
recordings for evaluation of spike-wave discharges. The end of the Maintenance Period will 
be Visit 9, or, if subjects withdraw early, the Early Termination Visit. Subjects may be 
eligible for participation in the additional open-label study (SP848) if they have completed 
the Maintenance Period and are taking a minimum dose of 4mg/kg/day for subjects 
weighing <50kg, and 200mg/day (tablets/oral solution) in subjects weighing ≥50kg. 
Subjects who do not complete the full 12 weeks of the Maintenance Period may still be 
eligible to enter the SP848 open-label study after consultation with the medical monitor. 
Subjects who choose not to participate in the open-label study or subjects who discontinue
due to other reasons will enter a 2- to 4-week Taper Period followed by a Safety
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 125 of 203
Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM and a Safety Follow-Up 
Telephone Contact 30 days (-1/+3 days) after the final dose of LCM. Dosing schedules 
for the Taper Period are provided in Table 7-4 and Table 7-5. Taper of LCM may not be 
required for some subjects who discontinue study medication prematurely, depending 
on the treatment option selected by the investigator in consultation with the subject 
and/or parent/legal representative.
A Data Monitoring Committee (DMC) will oversee the safety of the study.
Change #12
Section 5.1.1 Study duration per subject
The duration of treatment for an individual subject may be up to approximately 16 weeks 
excluding the Taper Period (due to the maximum allowed visit windows).
The study will consist of a 6-week prospective Baseline Period, followed by a 4-week 
Titration Period and a 12-week Maintenance Period. Subjects may be eligible to enter an 
additional open-label study (SP848) after completion of the Maintenance Period. Subjects 
who do not complete the full 12 weeks of the Maintenance Period may still be eligible to 
enter the SP848 open-label study after consultation with the medical monitor. Subjects who 
do not continue in the open-label study will enter up to a 4-week Taper Period followed by a 
1-week study drug-free Safety Period and Final Safety telephone contact. The total study 
duration for a subject will be up to a maximum of 27 weeks.
Has been changed to:
The duration of treatment for an individual subject may be up to approximately 18 weeks 
excluding the Taper Period.
The study will consist of a 6-week prospective Baseline Period, followed by a 6-week
Titration Period and a 12-week Maintenance Period. Subjects may be eligible to enter an 
additional open-label study (SP848) after completion of the Maintenance Period. Subjects 
who do not complete the full 12 weeks of the Maintenance Period may still be eligible to 
enter the SP848 open-label study after consultation with the medical monitor. Subjects who 
do not continue in the open-label study will enter a 2- to 4-week Taper Period followed by 
a Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM and a Safety 
Follow-Up Telephone Contact 30 days (-1/+3 days) after the final dose of LCM. The total 
study duration for a subject will be up to a maximum of 32 weeks.
Change #13
Section 5.1.2 Planned number of subjects and site(s)
It is planned to enroll approximately 50 subjects across 2 age cohorts. The first cohort will 
consist of approximately 40 subjects between 4 years and <18 years of age. The second 
cohort will consist of at least 10 subjects between 1 month and <4 years of age.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 126 of 203
Has been changed to:
Approximately 50 subjects will be enrolled. It is planned to enroll approximately 
40 subjects between 4 years and <18 years of age and at least 10 subjects between 1 month 
and <4 years of age.
Change #14
Section 5.1.3 Anticipated regions and countries
This study will be conducted at approximately 40 sites in Europe, USA, and other regions as 
deemed necessary.
Has been changed to:
This study will be conducted at approximately 50 sites in Europe, Russia, and North 
America, and other regions as deemed necessary.
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26 Feb 2015
Lacosamide
SP0966
of study assessments
e of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study 
and Unscheduled Visit)
Baseline Period 
(6 weeks)
Treatment (16 weeks)
End of Study 
Period
Unsched 
Visita
Titration Period (4 weeks)
Maintenance Period (12 weeks)
Taper 
Periodb
Safety 
Follow
-up
1
TC1
V2
V3
V4
V5
V6
TC2
V7
TC3
V8
TC4
V9/ETc
End of 
Taper 
Visit
TC5
At any 
time
6
-3
0
1
2
3
4
6
8
10
12
14
16
17-20
21
X
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X
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X
X
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X
X
X
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X
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X
X
X
X
X
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X
X
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X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 128 of 203
Table 5-1 Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study 
Period and Unscheduled Visit)
Assessments
Baseline Period 
(6 weeks)
Treatment (16 weeks)
End of Study 
Period
Unsched 
Visita
Titration Period (4 weeks)
Maintenance Period (12 weeks)
Taper 
Periodb
Safety 
Follow
-up
Visit
V1
TC1
V2
V3
V4
V5
V6
TC2
V7
TC3
V8
TC4
V9/ETc
End of 
Taper 
Visit
TC5
At any 
time
Week in study
-6
-3
0
1
2
3
4
6
8
10
12
14
16
17-20
21
Body weight and 
heightf
X
X
X
X
X
X
X
X
X
X
X
Neurological 
examination 
(complete)
X
X
X
Neurological 
examination (brief)
X
X
X
X
X
X
X
ECG (12-lead)g
X
X
X
X
X
X
X
X
X
X
Clinical 
chemistry/hematology
X
X
X
X
X
X
X
Xh
Endocrinology blood 
sample
X
X
Xh
Urinalysisi
X
X
X
X
X
X
Xj
Pregnancy testk
X
X
X
X
X
X
X
Tanner Stagel
X
X
Concomitant AED 
plasma concentration
m
X
X
X
LCM plasma 
concentrationm
X
X
X
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 129 of 203
Table 5-1 Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study 
Period and Unscheduled Visit)
Assessments
Baseline Period 
(6 weeks)
Treatment (16 weeks)
End of Study 
Period
Unsched 
Visita
Titration Period (4 weeks)
Maintenance Period (12 weeks)
Taper 
Periodb
Safety 
Follow
-up
Visit
V1
TC1
V2
V3
V4
V5
V6
TC2
V7
TC3
V8
TC4
V9/ETc
End of 
Taper 
Visit
TC5
At any 
time
Week in study
-6
-3
0
1
2
3
4
6
8
10
12
14
16
17-20
21
C-SSRSn
X
X
X
X
X
X
X
X
X
X
Xo
Clinical Global 
Impression of Change
X
Caregiver’s Global 
Impression of Change
X
Achenbach CBCLp
X
X
X
Bayley-IIIq
X
BRIEF-P/BRIEF
X
X
PedsQL
X
X
Contact IXRS
X
X
X
X
X
X
X
X
X
X
Dispense study 
medication
Xr
X
X
X
X
X
X
Xs
Study medication 
return
X
X
X
X
X
X
X
X
Dispense subject 
diary
X
X
X
X
X
X
X
X
Xs
Subject diary 
return/review
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Withdrawal criteria
X
X
X
X
X
X
X
X
X
X
X
X
X
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 130 of 203
Table 5-1 Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study 
Period and Unscheduled Visit)
Assessments
Baseline Period 
(6 weeks)
Treatment (16 weeks)
End of Study 
Period
Unsched 
Visita
Titration Period (4 weeks)
Maintenance Period (12 weeks)
Taper 
Periodb
Safety 
Follow
-up
Visit
V1
TC1
V2
V3
V4
V5
V6
TC2
V7
TC3
V8
TC4
V9/ETc
End of 
Taper 
Visit
TC5
At any 
time
Week in study
-6
-3
0
1
2
3
4
6
8
10
12
14
16
17-20
21
AE reporting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of 
epilepsy surgery
X
Changes in VNS 
settings
X
X
X
X
X
X
X
X
X
X
X
Health care resource 
use
X
X
X
X
X
X
X
X
X
X
X
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; BRIEF-P/BRIEF=Behavior Rating Inventory of Executive Function-Preschool version/ 
Behavior Rating Inventory of Executive Function; CBCL=Child Behavior Checklist; C-SSRS=Columbia Suicide Severity Rating Scale; 
ECG=electrocardiogram; EEG=electroencephalogram; ET=Early Termination Visit; IXRS= interactive voice/web response system; LCM=lacosamide; 
PedsQL=Pediatric Quality of Life Inventory; TC=telephone contact; V=Visit; VNS=vagus nerve stimulation
Note: For all visits a time window of ±2 days relative to Visit 2 (Baseline Period) is applicable. The schedule above displays the maximum possible study
duration for a subject.
a Unscheduled Visits may be performed at any time after Visit 1, at the discretion of the investigator. In addition to the required assessments indicated in the 
schedule above, further assessments can be completed as needed and may include ECG, laboratory tests, physical examination, neurological examination, 
etc. 
b The recommended Taper Period duration for subjects taking the tablet formulation is 2 weeks, but a slower taper over 4 weeks may be permitted if 
medically necessary. The duration of the Taper Period for the oral solution formulation is 4 weeks. The End of Taper Visit will occur at the end of the last 
week of the Taper Period.
c At the end of Visit 9 or at ET, all subjects who complete the Maintenance Period and whose daily dose was at least 6mg/kg/day for subjects weighing 
≤30kg, 4mg/kg/day for subjects weighing >30kg to ≤50kg, and 200mg/day (tablets/oral solution) in subjects weighing >50kg will be offered the 
opportunity to enroll in an additional open-label extension study, SP848. Visit 9 or the ET Visit of SP0966 will also serve as Visit 1 for SP848. Subjects 
who do not complete the full 12 weeks of the Maintenance Period may still be eligible to enter the SP848 open-label study after consultation with the 
medical monitor. Subjects who do not continue in the open-label extension study will complete the End of Study procedures that include up to a 4-week 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 131 of 203
Table 5-1 Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study 
Period and Unscheduled Visit)
Assessments
Baseline Period 
(6 weeks)
Treatment (16 weeks)
End of Study 
Period
Unsched 
Visita
Titration Period (4 weeks)
Maintenance Period (12 weeks)
Taper 
Periodb
Safety 
Follow
-up
Visit
V1
TC1
V2
V3
V4
V5
V6
TC2
V7
TC3
V8
TC4
V9/ETc
End of 
Taper 
Visit
TC5
At any 
time
Week in study
-6
-3
0
1
2
3
4
6
8
10
12
14
16
17-20
21
LCM taper followed by a 1-week Safety Follow-up Period and Final Safety telephone contact.
d Subject or caregiver (including parent/legal guardian) will be asked how many seizures the subject has had over the past 4 weeks as a historical baseline.
e Ambulatory EEG to begin on the morning prior to the visit eg, the day before Visit 2.
f Height will only be recorded at study visits where a complete physical examination is performed. Height is not required at an Unscheduled Visit.
g Two interpretable 12-lead ECG recordings will be performed approximately 20 to 30 minutes apart prior to any blood draws and vital sign assessments and, 
if possible, with the subject in the supine position for 5 minutes preceding the ECG recordings. Recordings should be performed at least 15 minutes after 
the removal of scalp electrodes used for the 24-hour ambulatory EEG recordings at Visit 2, Visit 6, and Visit 9 or the ET Visit.
h If no abnormality is observed in the laboratory blood samples from the previous visit, this End of Taper assessment does not have to be performed.
i For subjects aged 5 to 17 years.
j If no abnormality is observed in the 2 previous urinalysis tests, this End of Taper assessment will not need to be performed.
k For female subjects of childbearing potential, a serum pregnancy test will be performed at Visit 1, Visit 9 or the ET Visit, and the End of Taper Visit. A 
urine dipstick pregnancy test will be performed at Visit 2, Visit 6, Visit 7, and Visit 8.
l The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study.
m Blood samples for analysis of concomitant AED plasma concentrations and LCM will be drawn along with clinical chemistry and hematology samples;
predose at Visit 2 and postdose at Visit 6 and Visit 9 or the ET Visit.
n The C-SSRS will be completed for all subjects ≥6 years of age. 
o If the Unscheduled Visit is due to an AE, then the C-SSRS is required.
p The Achenbach CBCL: CBCL/1½ -5 for pediatric subjects from 18 months to 5 years 11 months and CBCL/6-18 for pediatric subjects 6 years and older; to 
be completed by the parent(s)/legal representative(s) (estimated completion time 45 minutes). The same scale will be completed again by the same 
parent(s)/legal representative(s) later in the open-label study, SP848 (if applicable). 
q Bayley Scales of Infant and Toddler Development®, Third Edition for pediatric subjects <18 months of age at Baseline enrolled in English-speaking 
countries.
r At the end of Visit 2, subjects should take the first dose of study medication in the clinic.
s For subjects entering Taper Period and not SP848.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 132 of 203
Has been changed to:
Table 5‒1:Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study Period and 
Unscheduled Visit)
Assessments
Baseline 
Period 
(6 weeks)
Treatment (18 weeks)
End of Study Period
Unsched 
Visita
Titration Period (6 weeks)
Maintenance Period (12 weeks)
Taper 
Period
(2-4 weeks)b
Safety 
Follow-Up
(30 days)
Visit
V1
TC1
V2
TC2
V3
TC3
V4c
V5c
End of 
Titrat
V6
TC4
V7
TC5
V8
TC6
V9/
ETd TC7e
End 
of 
Taper 
Visitf
Safety 
FU 
Visitg
Safety 
FU 
TCg
At any 
time
Week in study
-6
-3
Day 
1
1
2
3
4
5
6
8
10
12
14
16
18
19
20-22
22-24
24-26
Informed consent
X
Inclusion/exclusion 
criteria
X
X
X
Medical history
X
Seizure historyh
X
EEG (24h 
monitoring)i
X
X
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant AEDs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physical 
examination 
(complete)
X
X
X
X
Physical 
examination (brief)
X
X
X
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 133 of 203
Table 5‒1:Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study Period and 
Unscheduled Visit)
Assessments
Baseline 
Period 
(6 weeks)
Treatment (18 weeks)
End of Study Period
Unsched 
Visita
Titration Period (6 weeks)
Maintenance Period (12 weeks)
Taper 
Period
(2-4 weeks)b
Safety 
Follow-Up
(30 days)
Visit
V1
TC1
V2
TC2
V3
TC3
V4c
V5c
End of 
Titrat
V6
TC4
V7
TC5
V8
TC6
V9/
ETd TC7e
End 
of 
Taper 
Visitf
Safety 
FU 
Visitg
Safety 
FU 
TCg
At any 
time
Week in study
-6
-3
Day 
1
1
2
3
4
5
6
8
10
12
14
16
18
19
20-22
22-24
24-26
Vital signs (BP and 
pulse rate, including 
orthostatic 
assessments in 
ambulatory 
subjects)
X
X
X
X
X
X
X
X
X
X
X
X
Body weight and 
heightj
X
X
X
X
X
X
X
X
X
X
X
X
Head 
circumference
X
X
Neurological 
examination 
(complete)
X
X
X
X
Neurological 
examination (brief)
X
X
X
ECG (12-lead)k
X
X
X
X
X
X
X
X
X
X
Xl
Clinical chemistry/
hematology
X
X
X
X
Xl
X
X
Xl
Endocrinology
X
X
X
Xl
Urinalysism
X
X
X
X
X
Xl
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 134 of 203
Table 5‒1:Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study Period and 
Unscheduled Visit)
Assessments
Baseline 
Period 
(6 weeks)
Treatment (18 weeks)
End of Study Period
Unsched 
Visita
Titration Period (6 weeks)
Maintenance Period (12 weeks)
Taper 
Period
(2-4 weeks)b
Safety 
Follow-Up
(30 days)
Visit
V1
TC1
V2
TC2
V3
TC3
V4c
V5c
End of 
Titrat
V6
TC4
V7
TC5
V8
TC6
V9/
ETd TC7e
End 
of 
Taper 
Visitf
Safety 
FU 
Visitg
Safety 
FU 
TCg
At any 
time
Week in study
-6
-3
Day 
1
1
2
3
4
5
6
8
10
12
14
16
18
19
20-22
22-24
24-26
Pregnancy testn
X
X
X
X
X
X
X
X
X
X
X
Tanner Stageo
X
X
Concomitant AED 
plasma concentrationp
X
X
LCM plasma 
concentrationp
X
X
C-SSRSq
X
X
X
X
X
X
X
X
X
X
X
Xr
Clinical Global 
Impression of 
Change
X
Caregiver’s Global 
Impression of 
Change
X
Achenbach CBCLs
X
X
X
Bayley-IIIt
X
BRIEF-P/BRIEFu
X
X
PedsQLv
X
X
Contact IXRS
X
X
X
X
X
X
X
X
X
X
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2


UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 135 of 203
Table 5‒1:Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study Period and 
Unscheduled Visit)
Assessments
Baseline 
Period 
(6 weeks)
Treatment (18 weeks)
End of Study Period
Unsched 
Visita
Titration Period (6 weeks)
Maintenance Period (12 weeks)
Taper 
Period
(2-4 weeks)b
Safety 
Follow-Up
(30 days)
Visit
V1
TC1
V2
TC2
V3
TC3
V4c
V5c
End of 
Titrat
V6
TC4
V7
TC5
V8
TC6
V9/
ETd TC7e
End 
of 
Taper 
Visitf
Safety 
FU 
Visitg
Safety 
FU 
TCg
At any 
time
Week in study
-6
-3
Day 
1
1
2
3
4
5
6
8
10
12
14
16
18
19
20-22
22-24
24-26
Dispense LCM
Xw
X
X
X
X
X
X
Xx
LCM return
X
X
X
X
X
X
X
X
Dispense subject 
diary
X
X
X
X
X
X
X
X
Xx
Subject diary 
return/reviewy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Withdrawal criteria
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
AE reporting
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Assessment of 
epilepsy surgery
X
VNS assessmentz
X
X
X
X
X
X
X
X
X
X
X
X
Health care resource 
use
X
X
X
X
X
X
X
X
X
X
AE=adverse event; AED=antiepileptic drug; BP=blood pressure; BRIEF-P/BRIEF=Behavior Rating Inventory of Executive Function-Preschool 
Version/Behavior Rating Inventory of Executive Function; CBCL=Child Behavior Checklist; C-SSRS=Columbia Suicide Severity Rating Scale; 
ECG=electrocardiogram; EEG=electroencephalogram; ET=Early Termination; FU=Follow-Up; IXRS= interactive voice/web response system; 
LCM=lacosamide; PedsQL=Pediatric Quality of Life Inventory; TC=telephone contact; Titrat=Titration; V=Visit; VNS=vagus nerve stimulation
Note: For all visits outside of the Safety Follow-Up Period, a time window of ±2 days relative to Visit 2 (Titration Period) is applicable. The schedule above 
displays the maximum possible study duration for a subject.
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2


UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 136 of 203
Table 5‒1:Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study Period and 
Unscheduled Visit)
Assessments
Baseline 
Period 
(6 weeks)
Treatment (18 weeks)
End of Study Period
Unsched 
Visita
Titration Period (6 weeks)
Maintenance Period (12 weeks)
Taper 
Period
(2-4 weeks)b
Safety 
Follow-Up
(30 days)
Visit
V1
TC1
V2
TC2
V3
TC3
V4c
V5c
End of 
Titrat
V6
TC4
V7
TC5
V8
TC6
V9/
ETd TC7e
End 
of 
Taper 
Visitf
Safety 
FU 
Visitg
Safety 
FU 
TCg
At any 
time
Week in study
-6
-3
Day 
1
1
2
3
4
5
6
8
10
12
14
16
18
19
20-22
22-24
24-26
a Unscheduled Visits may be performed at any time after Visit 1, at the discretion of the investigator. In addition to the required assessments indicated in the 
schedule above, the investigator can perform further assessments based on his/her clinical judgment and the medical needs of the subject (eg, 
assessments of ECG, laboratory tests, physical examination, neurological examination, etc).
b The recommended Taper Period duration is up to a maximum of 4 weeks, but a slower or faster taper may be permitted if medically necessary. The End of 
Taper Visit will occur at the end of the last week of the Taper Period.
c Visits 4 and 5 are optional and will only be required if a subject requires further LCM dose adjustment.
d At the end of Visit 9 or at ET, all subjects who complete the Maintenance Period and whose daily dose was at least 4mg/kg/day for subjects weighing <50kg, 
and 200mg/day (tablets/oral solution) for subjects weighing ≥50kg will be offered the opportunity to enroll in an additional open-label extension study, SP848. 
Visit 9 or the ET Visit of SP0966 will also serve as Visit 1 for SP848. Subjects who do not complete the full 12 weeks of the Maintenance Period may still be 
eligible to enter the SP848 open-label study after consultation with the medical monitor. Subjects who do not continue in the open-label extension study will 
complete the End of Study procedures that include a 2- to 4-week LCM taper followed by a 30-day Safety Follow-Up Period. Taper of LCM may not be 
required for some subjects who discontinue study medication prematurely, depending on the treatment option selected by the investigator in 
consultation with the subject and/or parent/legal representative.
e A telephone contact (T7) will be conducted at the end of the first week of the Taper Period.
f Each subject will have only 1 Taper Visit. The Taper Visit will be scheduled at the end of the Taper Period (Week 20, Week 21, or Week 22, 
depending on dose level achieved; see Table 7-4 and Table 7-5). A time window of ±2 days relative to Visit 2 (Titration Period) is applicable. The study 
week numbers provided are for subjects who complete the Maintenance Period and enter the Taper Period. The study week numbers provided do not 
apply to subjects who enter the Taper Period at other times.
g The Safety Follow-Up Visit will occur 2 weeks (±2 days) after the final dose of LCM. The Safety Follow-Up Telephone Contact will occur 30 days 
(-1/+3 days) after the final dose of LCM.
h Subject or caregiver (including parent/legal representative) will be asked how many seizures the subject has had over the past 4 weeks as a historical baseline.
i Ambulatory EEG to begin on the morning prior to the visit eg, the day before Visit 2, Visit 6, and Visit 9.
j Height will only be recorded at study visits where a complete physical examination is performed. Height is not required at an Unscheduled Visit.
k Two interpretable 12-lead ECG recordings will be performed approximately 20 to 30 minutes apart prior to any blood draws and vital sign assessments. The 
subject should rest in the supine position for approximately 5 minutes before the recordings and during the recordings, if possible. Recordings should 
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2


UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 137 of 203
Table 5‒1:Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study Period and 
Unscheduled Visit)
Assessments
Baseline 
Period 
(6 weeks)
Treatment (18 weeks)
End of Study Period
Unsched 
Visita
Titration Period (6 weeks)
Maintenance Period (12 weeks)
Taper 
Period
(2-4 weeks)b
Safety 
Follow-Up
(30 days)
Visit
V1
TC1
V2
TC2
V3
TC3
V4c
V5c
End of 
Titrat
V6
TC4
V7
TC5
V8
TC6
V9/
ETd TC7e
End 
of 
Taper 
Visitf
Safety 
FU 
Visitg
Safety 
FU 
TCg
At any 
time
Week in study
-6
-3
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1
1
2
3
4
5
6
8
10
12
14
16
18
19
20-22
22-24
24-26
be performed at least 15 minutes after the removal of scalp electrodes used for the 24-hour ambulatory EEG recordings at Visit 2, Visit 6, and Visit 9 or the ET 
Visit.
l The assessment will only be required for subjects with an abnormal value (clinical chemistry, hematology, or endocrinology) or reading (ECG) at the 
previous clinic visit.
m For subjects aged 5 to 17 years.
n For female subjects of childbearing potential, a serum pregnancy test will be performed at Visit 1, Visit 9 or the ET Visit, and the End of Taper Visit. A 
serum pregnancy test will also be performed at the Safety Follow-Up Visit only if blood is collected for other laboratory tests. If no blood is collected 
for other assessments, then a urine pregnancy test will be performed. A urine pregnancy test will be performed at all other visits, as scheduled in 
Table 5-1.
o The Tanner Stage will be performed only for subjects who are pubescent at Visit 1 or who will enter puberty during the course of the study.
p Blood samples for analysis of concomitant AED plasma concentrations and LCM plasma concentration will be drawn along with clinical chemistry and 
hematology samples; predose at Visit 2 and postdose at Visit 9 or the ET Visit.
q The C-SSRS will be completed for all subjects ≥6 years of age.
r If the Unscheduled Visit is due to an AE, then the C-SSRS is required.
s The Achenbach CBCL: CBCL/1½-5 for pediatric subjects from 18 months to 5 years 11 months and CBCL/6-18 for pediatric subjects aged 6 years and older; 
to be completed by the parent(s)/legal representative(s) (estimated completion time 45 minutes). For each subject, the same version of the scale that was 
completed at Visit 2 (CBCL/1½-5 or CBCL/6-18) should be maintained for the duration of the study and should be completed by the same 
parent/legal representative. The same scale should be completed again by the same parent(s)/legal representative(s) later in the open-label study, SP848 (if 
applicable). The Achenbach CBCL will be used only in countries where a translated version is available.
t Bayley Scales of Infant and Toddler Development®, Third Edition for pediatric subjects <18 months of age at Baseline enrolled in English-speaking countries.
u The BRIEF-P should be used for subjects who are ≥2 years to <5 years of age at Visit 2, and the BRIEF should be used for subjects who are ≥5 years 
of age at Visit 2. The same version of the scale that was completed at Visit 2 (BRIEF P or BRIEF) should be maintained for each subject for the 
duration of the study. The BRIEF P and BRIEF will be used only in countries where a translated version is available.
v The version of the PedsQL used at Visit 2 should be consistent with the subject’s age at Visit 2 and should be maintained for each subject for the 
duration of the study. The PedsQL will be used only in countries where a translated version is available.
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2


UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 138 of 203
Table 5‒1:Schedule of study assessments (Baseline Period, Titration Period, Maintenance Period, End of Study Period and 
Unscheduled Visit)
Assessments
Baseline 
Period 
(6 weeks)
Treatment (18 weeks)
End of Study Period
Unsched 
Visita
Titration Period (6 weeks)
Maintenance Period (12 weeks)
Taper 
Period
(2-4 weeks)b
Safety 
Follow-Up
(30 days)
Visit
V1
TC1
V2
TC2
V3
TC3
V4c
V5c
End of 
Titrat
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V7
TC5
V8
TC6
V9/
ETd TC7e
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of 
Taper 
Visitf
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FU 
Visitg
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FU 
TCg
At any 
time
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-6
-3
Day 
1
1
2
3
4
5
6
8
10
12
14
16
18
19
20-22
22-24
24-26
w At the end of Visit 2, subjects should take the first dose of LCM in the clinic.
x For subjects entering Taper Period and not entering SP848.
y The subject diary will be dispensed at Visit 1. At all subsequent visits, the subject and/or legal representative(s) will be reminded to complete the diary 
on a daily basis.
z As applicable, VNS assessment will only be performed for subjects with an implanted VNS device at Visit 1.
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2


UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 139 of 203
Change #16
Section 5.3 Schematic diagram
Figure 5-1
Schematic diagram - LCM tablet dosing and taper schedule
Titration Period
(4 Weeks)
Maintenance Period
(12 weeks)
Taper Period 
(2 Weeks - depending on 
dose achieveda)
Baseline Period
400mg/day
300mg/day
200mg/day 
200mg/day
100mg/day 
0
Weeks
Week
Week
Week
Week
Weeks
Week
Week 
-6 to 0
1
2
3
4
5-16
17
18
a Schematic shows standard 2-week Taper Period. If medically necessary, a slow taper over 4 weeks, with decrements of LCM 100mg/day per 
week may be permitted.
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2


UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 140 of 203
Figure 5-2
Schematic diagram - LCM oral solution dosing and taper schedule
Titration Period
(4 Weeks)
Maintenance Period
(12 weeks)
Taper Period 
(up to 4 Weeks - depending on dose achieved)
Baseline 
Period
12mg/kg/day 
or
8mg/kg/day
9mg/kg/day 
or 
6mg/kg/day
9mg/kg/day 
or 
6mg/kg/day
6mg/kg/day 
or 
4mg/kg/day
6mg/kg/day 
or 
4mg/kg/day
3mg/kg/day 
or 
2mg/kg/day
3mg/kg/day 
or 
2mg/kg/day
0
Weeks
Week
Week
Week
Week
Weeks
Week
Week
Week
Week
-6 to 0
1
2
3
4
5-16
17
18
19
20
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2


UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 141 of 203
Has been changed to:
Figure 5-1:
Schematic diagram - LCM dosing and taper schedule for subjects <50kg receiving oral solution 
formulation
V1
  TC1
V2
V3-V5 and TC2-TC3
V6
V7 –V8 and TC4-T6
V9
TC7-End of Taper Visit
Baseline Period
Titration Perioda
Maintenance Periodb
Taper Periodc
12mg/kg/day 
10mg/kg/day 
8mg/kg/day 
9mg/kg/day 
Subjects
6mg/kg/day 
6mg/kg/day 
<50kg
4mg/kg/day 
4mg/kg/day 
2mg/kg/day 
2mg/kg/day 
Taper based on the maximum dose 
achieved during the Maintenance 
Period
Weeks
Week
Week
Week
Week
Week
Week
Week 7 through
Week
Week
Week
Week
-6 to 0
1
2
3
4
5
6
Week 18
19
20
21
22
TC=Telephone Contact; V=Visit 
Note: LCM dosing is designated as “mg/kg/day” 
a During Titration Period dosage may be adjusted up or down based on investigator’s clinical judgment. 
b Dose reached at the end of Titration Period will be taken throughout Maintenance Period. Subjects may be eligible for participation in the additional 
open-label study (SP848) if they have completed the Maintenance Period and are taking a minimum dose of 4mg/kg/day. Subjects will begin SP848 on 
the LCM dose they achieved in the Maintenance Period in SP0966. Subjects who do not complete the full 12 weeks of the Maintenance Period may 
still be eligible to enter the SP848 open-label study after consultation with the medical monitor.
c Subjects with doses <3mg/kg/day do not need to taper. See Table 7-5 for exact taper schedule. Taper is not required for subjects participating in the 
additional open-label study (SP848). A slower or faster taper is permitted if medically necessary. Taper of LCM may not be required for some 
subjects who discontinue study medication prematurely, depending on the treatment option selected by the investigator in consultation with the 
subject and/or parent/legal representative. The Taper Period is followed by a Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM 
and a Safety Follow-Up Telephone Contact 30 days (-1/+3 days) after the final dose of LCM.
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2


UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 142 of 203
Figure 5-2:
Schematic diagram - LCM dosing and taper schedule for subjects ≥50kg receiving oral solution or 
tablet formulation
V1
  TC1
V2
V3-V5 and TC2-TC3
V6
V7 –V8 and TC4-T6
V9
TC7-End of Taper Visit
Baseline Period
Titration Perioda
Maintenance Periodb
Taper Periodc
600mg/day
500mg/day
400mg/day
500mg/day
Subjects
300mg/day
300mg/day
≥50kg
200mg/day
200mg/day
100mg/day 
100mg/day
Taper based on the maximum dose 
achieved during the Maintenance 
Period
Weeks
Week
Week
Week
Week
Week
Week
Week 7 through
Week
Week
Week
Week
-6 to 0
1
2
3
4
5
6
Week 18
19
20
21
22
TC=Telephone Contact; V=Visit 
Note: LCM dosing is designated as “mg/day” 
a During Titration Period dosage may be adjusted up or down based on investigator’s clinical judgment.
b Dose reached at the end of Titration Period will be taken throughout Maintenance Period. Subjects may be eligible for participation in the additional 
open-label study (SP848) if they have completed the Maintenance Period and are taking a minimum dose of 200mg/day (tablets/oral solution). 
Subjects will begin SP848 on the LCM dose they achieved in the Maintenance Period in SP0966. Subjects who do not complete the full 12 weeks of the 
Maintenance Period may still be eligible to enter the SP848 open label study after consultation with the medical monitor.
c Subjects with doses <150mg/day do not need to taper. See Table 7-5 for exact taper schedule. Taper is not required for subjects participating in the 
additional open-label study (SP848). A slower or faster taper is permitted if medically necessary. Taper of LCM may not be required for some 
subjects who discontinue study medication prematurely, depending on the treatment option selected by the investigator in consultation with the 
subject and/or parent/legal representative. The Taper Period is followed by a Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM 
and a Safety Follow-Up Telephone Contact 30 days (-1/+3 days) after the final dose of LCM.
k
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2


UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 143 of 203
Change #17
Section 5.4 Rationale for study design and selection of dose
Based on the currently available LCM pediatric safety and PK data from SP847 and SP1047, 
as well as on information available in the medical literature, the dosing recommendations for 
SP0966 are as follows:
•
LCM dosing should aim to achieve LCM plasma concentrations equivalent to the average 
steady-state LCM plasma concentration reached after a LCM 400mg/day dose 
administration in adult studies, which is approximately 8μg/mL.
•
A weight-based dosing scheme is recommended:
−
Subjects ≤30kg: LCM 12mg/kg/day (oral solution)
−
Subjects >30kg to ≤50kg: LCM 8mg/kg/day (oral solution, up to a maximum of 
LCM 400mg/day)
−
Subjects weighing >50kg: 400mg/day (tablets/oral solution)
Has been changed to:
Based on the currently available LCM pediatric safety and PK data from SP847 and SP1047, 
as well as on information available in the medical literature, the dosing recommendations for 
SP0966 are as follows:
•
Lacosamide dosing should aim to achieve LCM plasma concentrations equivalent to the 
average steady-state LCM plasma concentration reached after a LCM 200 to 600mg/day 
dose administration in adult studies.
•
A weight-based flexible dosing scheme is recommended:
−
Subjects <50kg: LCM 4-12mg/kg/day (oral solution)
−
Subjects ≥50kg: LCM 200 to 600mg/day (tablets/oral solution)
Change #18
Section 6.1 Inclusion criteria
1. A signed informed consent has been obtained from the parent/guardian and assent has 
been obtained from the subject (when possible or as required according to local 
Institutional Review Boards [IRBs]/Independent Ethics Committees [IECs]).
2. Subject and caregiver (which may be a parent, a legal guardian, or other caregiver) are 
willing and able to comply with all study requirements including maintaining a daily 
seizure diary.
3. Subject is male or female, ≥1 month to <18 years of age. (Note, until the LCM dose range 
has been defined in subjects <4 years of age, only subjects ≥4 years of age will be 
enrolled.) For preterm infants <1 year old, the corrected gestational age should be used 
when determining eligibility. The generally accepted definition of corrected gestational 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 144 of 203
age, which is calculated by subtracting the number of weeks born before 37 weeks of 
gestation from the chronological age, will be used for this study.
7. Vagal nerve stimulation is allowed and will not be counted as a concomitant AED. Vagal 
nerve stimulation (implanted for at least 6 months and stable for at least 4 weeks before 
Visit 1) must be kept stable during the Baseline Period and the Maintenance Period.
8. Body weight at Visit 1 is at least 5kg for infants.
9. Females with childbearing potential must have a negative pregnancy test at Visit 1.
Has been changed to:
1. A signed informed consent has been obtained from the parent/legal representative and 
assent has been obtained from the subject (when possible or as required according to local 
Institutional Review Boards [IRBs]/Independent Ethics Committees [IECs]).
2. Subject and caregiver (which may be a parent, a legal representative, or other caregiver) 
are willing and able to comply with all study requirements including maintaining a daily 
seizure diary.
3. Subject is male or female, ≥1 month to <18 years of age. (Note, until the LCM dose range 
has been defined in subjects <2 years of age based on SP847, only subjects ≥2 years of 
age will be enrolled.) For preterm infants <1 year old, the corrected gestational age should 
be used when determining eligibility. The generally accepted definition of corrected 
gestational age, which is calculated by subtracting the number of weeks born before 
37 weeks of gestation from the chronological age, will be used for this study.
7. Vagal nerve stimulation is allowed and will not be counted as a concomitant AED. The 
VNS device must be implanted for at least 6 months before Visit 1, and the device 
settings must be stable for at least 4 weeks before Visit 1 and be kept stable during 
the Baseline Period and the Treatment Period. Use of the VNS device magnet is 
allowed.
8. Body weight at Visit 1 is at least 4kg for infants.
9. Females of childbearing potential must have a negative pregnancy test at Visit 1.
Change #19
Section 6.1 Inclusion criteria
The following criterion has been added:
10. Subjects with West Syndrome are eligible if Baseline EEG demonstrates 
hypsarrhythmia despite treatment with at least 2 AEDs appropriate for the 
treatment of this syndrome.
Change #20
Section 6.2 Exclusion criteria
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 145 of 203
1. Subject has previously participated in this study or subject has previously been assigned 
to any treatment in a LCM study.
5. Subject has exclusively typical absence (Type IIA1) or atypical absence (Type IIA2) 
seizures (no other generalized seizure types are reported).
8. Subject has a lifetime history of suicide attempt (including an actual attempt, interrupted 
attempt, or aborted attempt), or has suicidal ideation in the past 6 months as indicated by 
a positive response (“Yes”) to either Question 4 or Question 5 of the Columbia Suicide 
Severity Rating Scale (C-SSRS) at Screening. 
17. Subject has a clinically relevant ECG abnormality, in the opinion of the principal 
investigator (ie, second or third degree heart block at rest or a QT prolongation greater 
than 450ms).
21. Subject is a female who is pregnant or nursing, and/or a female of childbearing potential 
(or who achieves menarche during the study) who does not practice 2 combined methods 
of contraception, unless sexually abstinent, for the duration of the study. Male subject 
who does not agree to practice 2 combined methods of contraception (eg, condom, 
spermicide), unless sexually abstinent, for the duration of the study.
−
Medically acceptable contraceptive method includes oral or depot contraceptive 
treatment with at least 30μg ethinylestradiol per intake (or 50μg if associated with 
carbamazepine [or other strong enzyme inducers, eg, phenobarbital, primidone, 
oxcarbazepine]), which must be used in conjunction with a barrier method. Sexual 
abstinence is also an acceptable method of contraception.
−
The subject must understand the consequences and potential risks of inadequately 
protected sexual activity, be educated about and understand the proper use of 
contraceptive methods, and undertake to inform the investigator of any potential 
change in status. Females of childbearing potential must have a negative pregnancy 
test at the Screening Visit (Visit 1).
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 146 of 203
Has been changed to:
1.
Subject has previously participated in this study, subject has been assigned to LCM in 
a previous LCM study, or subject has ever received LCM.
5.
Subject has exclusively typical absence (Type IIA1) or atypical absence (Type IIA2) 
seizures (no other generalized seizure types are reported), or has only partial-onset 
seizures (Type I).
8.
Subject ≥6 years of age has a lifetime history of suicide attempt (including an actual 
attempt, interrupted attempt, or aborted attempt), or has suicidal ideation in the past 
6 months as indicated by a positive response (“Yes”) to either Question 4 or Question 5 
of the Columbia Suicide Severity Rating Scale (C-SSRS) at Screening.
17. Subject has a clinically relevant ECG abnormality, in the opinion of the principal 
investigator (ie, second or third degree heart block at rest or a corrected QT interval 
[QTc] greater than 450ms).
21. Female subject who is pregnant or nursing, and/or a female subject of childbearing 
potential who is not surgically sterile or does not practice 1 highly effective method 
of contraception (according to International Conference on Harmonisation [ICH] 
guidance defined as those that result in a failure rate of less than 1% per year when 
used consistently and correctly), unless sexually abstinent, for the duration of the 
study. Female subject of childbearing potential taking enzyme inducing 
antiepileptic drugs (EI-AEDs) (carbamazepine, phenytoin, barbiturates, primidone, 
topiramate, oxcarbazepine) who is not surgically sterile or does not practice 
1 highly effective method of contraception according to the World Health 
Organization recommendation (ie, depot medroxyprogesterone acetate, 
norethisterone enantate, intrauterine devices, combined injectables, and 
progestogen implants) with administration of EI-AEDs or does not practice 
2 combined methods of contraception (ie, combined hormonal contraception plus 
barrier method with spermicidal agent), unless sexually abstinent, for the duration 
of the study.
Change #21
Section 6.3 Withdrawal criteria
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care.
All subjects discontinuing treatment with LCM for any reason should taper off LCM. It is 
recommended that the dosage be tapered off in weekly decrements of 2 mg/kg/day or 
3mg/kg/day (oral solution) or 200mg/day (tablet) (see Section 7.2). A slower taper is 
permitted if medically necessary. Whenever possible, these cases should be discussed with 
the medical monitor prior to withdrawing the subject from the study, especially in cases in 
which exit criteria have been met.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 147 of 203
All subjects who withdraw from the study due to an AE must be followed until resolution of 
the event or until the event is considered stable.
Subjects must be withdrawn from the study if any of the following events occur:
1. Subject experiences intolerable AEs, including clinically relevant abnormal laboratory 
findings that, in the opinion of the investigator, preclude further participation in the study.
2. The sponsor or a regulatory agency requests withdrawal of the subject.
3. Subject achieves menarche during the study and does not practice an acceptable method 
of contraception for the duration of the study (unless sexually abstinent).
4. Subject becomes pregnant, as evidenced by a positive pregnancy test.
5. A QTc interval of ≥500ms is confirmed by a cardiologist overread on any ECG.
6. Subject develops a second degree AV block while awake or develops a third degree AV 
block.
7. Subject is unwilling or unable to continue, or the parent/legal guardian is unwilling or 
unable to allow the subject to continue in the study.
8. Investigator decides that withdrawal from further participation would be in the subject’s 
best interest. 
9. Subject has a prolongation or worsening of overall seizure duration, frequency, type, or 
pattern considered by the investigator as serious enough to warrant discontinuation from 
the study.
10. Subject requires the use of rescue medication in excess of that permitted by the protocol.
11. In the case of liver function test (LFT) results of transaminases (AST, ALT, or both) 
≥3x ULN to <5x ULN and total bilirubin ≥2x ULN or transaminases (AST, ALT, or both) 
≥5x ULN, the study medication must be immediately discontinued and the subject 
withdrawn from the study. The LFTs will be repeated as soon as possible, and in no case 
>1 week later.
12. Subject has actual suicidal ideation as indicated by a positive response (“Yes”) to either 
Question 4 or Question 5 of the “Since Last Visit” version of the C-SSRS. The subject 
should be referred immediately to a Mental Healthcare Professional and must be 
withdrawn from the study.
Subjects may be withdrawn from the study if any of the following events occur:
1. Any clinically relevant change in medical or psychiatric condition (if in the opinion of the 
investigator, the condition warrants discontinuation from the study).
2. Subject requires a medication that is not permitted by the protocol (see Section 7.8).
3. Subject and/or delegated caregiver is unable to manage the completion of the diary or is 
noncompliant with study procedures or medication, in the opinion of the investigator.
4. Subject needs any alteration in AED daily dose or dosing frequency or VNS settings.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 148 of 203
5. Transaminases (AST, ALT, or both) ≥3x ULN to <5x ULN, in the presence of normal 
total bilirubin, will be repeated within a few days. If the repeat testing confirms the 
abnormality (ie, transaminases are ≥3x ULN to <5x ULN with normal bilirubin), then 
weekly monitoring of LFTs should continue until resolved (ie, <3x ULN or stable 
condition). The investigator is to decide whether or not to stop the study medication.
Has been changed to:
Subjects are free to withdraw from the study at any time, without prejudice to their continued 
care.
All subjects who withdraw from the study due to an AE must be followed until resolution of 
the event or until the event is considered stable.
Subjects must be withdrawn from the study if any of the following events occur:
1. Subject experiences intolerable AEs, including clinically relevant abnormal laboratory 
findings that, in the opinion of the investigator, preclude further participation in the study.
2. The sponsor or a regulatory agency requests withdrawal of the subject.
3. Female subject achieves menarche and does not practice contraception as provided 
in Exclusion Criterion 21, unless sexually abstinent.
4. Subject becomes pregnant, as evidenced by a positive pregnancy test.
5. Subject has QTc interval of ≥500ms that is confirmed by a cardiologist overread on any 
ECG.
6. Subject develops a second degree AV block while awake or develops a third degree AV 
block.
7. Subject is unwilling or unable to continue, or the parent/legal representative is unwilling 
or unable to allow the subject to continue in the study.
8. Investigator decides that withdrawal from further participation would be in the subject’s 
best interest. 
9. Subject has a prolongation or worsening of overall seizure duration, frequency, type, or 
pattern considered by the investigator as serious enough to warrant discontinuation from 
the study.
10. Subject uses rescue medication in excess of that permitted by the protocol.
11. Subject needs any alteration in AED daily dose or VNS settings.
12. In the case of liver function test (LFT) results of transaminases (AST, ALT, or both) 
≥3x ULN to <5x ULN and total bilirubin ≥2x ULN or transaminases (AST, ALT, or both) 
≥5x ULN, LCM must be immediately discontinued and the subject withdrawn from the 
study. The LFTs will be repeated as soon as possible, and in no case >1 week later.
13. For subjects ≥6 years of age, subject has actual suicidal ideation as indicated by a 
positive response (“Yes”) to either Question 4 or Question 5 of the “Since Last Visit” 
version of the C-SSRS. The subject should be referred immediately to a Mental 
Healthcare Professional and must be withdrawn from the study.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 149 of 203
Subjects may be withdrawn from the study if any of the following events occur:
1. Any clinically relevant change in medical or psychiatric condition (if in the opinion of the 
investigator, the change in condition warrants discontinuation from the study).
2. Subject requires a medication that is not permitted by the protocol (see Section 7.8).
3. Subject and/or delegated caregiver is unable to manage the completion of the diary or is 
noncompliant with study procedures or medication, in the opinion of the investigator.
4. Transaminases (AST, ALT, or both) ≥3x ULN to <5x ULN, in the presence of normal total 
bilirubin, will be repeated within a few days. If the repeat testing confirms the abnormality 
(ie, transaminases are ≥3x ULN to <5x ULN with normal bilirubin), then weekly 
monitoring of LFTs should continue until resolved (ie, <3x ULN or stable condition). The 
investigator is to decide whether or not to stop LCM.
Change #22
Section 7.2 Treatment(s) to be administered
At the end of the Baseline Period (completion of Visit 2), subjects who meet the eligibility 
criteria will commence a 4-week Titration Period. 
As described in Section 5.1, subjects will initiate treatment with LCM oral solution at 
2mg/kg/day or 3mg/kg/day, or LCM tablets at 100mg/day based on body weight. The dose 
will be titrated to a level to optimize tolerability and seizure control, not to exceed 
12mg/kg/day for subjects weighing ≤30kg, or 8mg/kg/day for subjects weighing >30kg to 
≤50kg, and 400mg/day (tablets/oral solution) in subjects weighing >50kg. Subjects will 
increase the LCM dose in a stepwise fashion on a weekly basis to optimize tolerability and 
seizure control. During the Titration period only, one back-titration step is permitted; once 
the dose of LCM has been back-titrated, the dose cannot be increased for the duration of the 
study (see Figure 5-1 and Figure 5-2).
If a subject does not achieve or require the maximum dose level (8mg/kg/day, 12mg/kg/day, 
or 400mg/day), then the highest optimized dose will be maintained until the end of the 
Titration Period. The Titration Period will last 4 weeks, regardless of the doses administered. 
Subjects who are not able to tolerate the minimum required dose (at least 6mg/kg/day for 
subjects weighing ≤30kg, 4mg/kg/day for subjects weighing >30kg to ≤50kg, or 
200mg/day [tablets/oral solution] for subjects weighting >50kg) of LCM (even after 
back-titration) will be withdrawn from the study. Study medication doses will be titrated 
according to the schedules presented in Table 7-1.
The maximum LCM dose is not to exceed 12mg/kg/day (oral solution) for subjects weighing 
≤30kg, 8mg/kg/day (oral solution) for subjects weighing >30kg to ≤50kg, and 
400mg/day (tablets/oral solution) in subjects weighing >50kg.
The planned doses for each week of the Titration Period for subjects taking the LCM oral 
solution and tablet formulations are displayed in Table 7-1.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 150 of 203
Table 7-1 Lacosamide dose titration during the Titration Period
Week
Study Medication Dose
Subjects weighing 
≤30kg
LCM 12mg/kg/day
(oral solution)
Subjects weighing 
>30kg to ≤50kg
LCM 8mg/kg/day
(oral solution)
Subjects weighing 
>50kg
LCM 400mg/day
(tablet)
1
3mg/kg/day
2mg/kg/day
100mg/day
2
6mg/kg/day
4mg/kg/day
200mg/day
3
9mg/kg/day
6mg/kg/day
300mg/day
4
12mg/kg/day
8mg/kg/day
400mg/day
At the end of the Titration Period (Visit 6), a 12-week Maintenance Period will begin.
Subjects must titrate to at least 6mg/kg/day for subjects weighing ≤30kg, 4mg/kg/day for 
subjects weighing >30kg to ≤50kg, or 200mg/day (tablets/oral solution) for subjects weighing 
>50kg in order to enter the Maintenance Period. Subjects will enter the Maintenance Period 
at the LCM dose achieved at the end of the Titration Period. No dose modification is 
permitted during the Maintenance Period. Subjects who require a change in dose during the 
Maintenance Period will be withdrawn from the study. 
Subjects may be eligible for participation in the additional open-label study (SP848) upon 
completion of the Maintenance Period and a minimum dose of 6mg/kg/day for subjects 
weighing ≤30kg, 4mg/kg/day for subjects weighing >30kg to ≤50kg, and 
200mg/day (tablets/oral solution) in subjects weighing >50kg. Subjects will begin SP848 on 
the LCM dose they were taking in the Maintenance Period in SP0966. Subjects who do not 
complete the full 12 weeks of the Maintenance Period may still be eligible to enter the SP848 
open-label study after consultation with the medical monitor.
Subjects who choose not to participate in the open-label study, subjects who are only able to 
tolerate the lowest LCM dose (100mg/day for the tablet formulation, 3mg/kg/day or 
2mg/kg/day for the oral solution formulation), or subjects who are discontinuing due to other 
reasons will enter up to a 4-week Taper Period followed by a 1-week study drug-free Safety 
Period and Final Safety telephone contact. The doses to be used during the Taper Period and 
the duration of the Taper Period will depend on the dose maintained during the Maintenance 
Period. For subjects taking the LCM oral solution, weekly decrements of either 2mg/kg/day 
or 3mg/kg/day (based on body weight) are recommended during the Taper Period. For 
subjects taking the LCM tablets, a weekly decrement of 200mg/day per week during the 
Taper Period is recommended. 
Table 7-2, Table 7-3 and Table 7-4 display the recommended LCM dose reductions during 
the Taper Period for the LCM oral solution and tablet formulations, respectively. 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 151 of 203
Table 7-2 Recommended LCM dose taper for oral solution formulation for 
subjects weighing ≤30kg
Maximum LCM dose 
maintained
Taper schedule
Week 17
Week 18
Week 19
Week 20
12mg/kg/day
9mg/kg/day
6mg/kg/day
3mg/kg/day
0
9mg/kg/day
6mg/kg/day
3mg/kg/day
0
-
6mg/kg/day
3mg/kg/day
0
-
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3mg/kg/day
0
-
-
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LCM=lacosamide
Table 7-3 Recommended LCM dose taper for oral solution formulation for 
subjects weighing >30kg to ≤50kg
Maximum LCM dose 
maintained
Taper schedule
Week 17
Week 18
Week 19
Week 20
8mg/kg/day
6mg/kg/day
4mg/kg/day
2mg/kg/day
0
6mg/kg/day
4mg/kg/day
2mg/kg/day
0
-
4mg/kg/day
2mg/kg/day
0
-
-
2mg/kg/day
0
-
-
-
LCM=lacosamide
Table 7-4 Recommended LCM dose taper for tablet formulation for subjects 
weighing >50kg
Maximum LCM dose 
maintained
Taper schedule
Week 17
Week 18
400mg/day
200mg/day
0
300mg/day
100mg/day
0
200mg/day
0
-
100mg/day
0
-
LCM=lacosamide
All subjects discontinuing treatment with LCM for any reason should taper off LCM. It is 
recommended that the dosage be tapered off in weekly decrements of either 2mg/kg/day or 
3mg/kg/day (based on body weight; oral solution) or 200mg/day (tablet). A slower taper is 
permitted if medically necessary. Whenever possible, these cases should be discussed with 
the medical monitor prior to withdrawing the subject from the study, especially in cases in 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 152 of 203
which exit criteria have been met. In case of an emergency, a faster taper is permitted after 
discussion with the medical monitor, whenever possible.
If subjects discontinue prematurely from the study, an Early Termination Visit will occur
where subjects will be instructed to taper their LCM dose as appropriate. Subjects who do not 
complete the full 12 weeks of the Maintenance Period may still be eligible to enter the SP848 
open-label study after consultation with the medical monitor.
Has been changed to:
Lacosamide will be administered orally bid (at approximately 12-hour intervals in the 
morning and in the evening). Administration of oral solution by feeding tube is permitted 
for subjects who are unable to swallow the oral solution.
At the end of the Baseline Period and completion of Visit 2, subjects who meet the eligibility 
criteria will commence a 6-week Titration Period (LCM dosing flexibility allowed based on 
tolerability). 
As described in Section 5.1, subjects will initiate treatment with LCM oral solution at 
2mg/kg/day, or LCM tablets at 100mg/day based on body weight. The dose will be titrated 
to a level to optimize tolerability and seizure control, not to exceed 12mg/kg/day (oral 
solution) for subjects weighing <50kg, or 600mg/day (tablets/oral solution) in subjects 
weighing ≥50kg. Subjects will increase the LCM dose in a stepwise fashion on a weekly 
basis to optimize tolerability and seizure control (see Figure 5-1 and Figure 5-2). During 
the Titration Period only, back-titration is permitted.
The planned doses for each week of the Titration Period for subjects taking the LCM 
oral solution and tablet formulations are displayed in Table 7-1.
Table 7-1 Lacosamide dose titration during the Titration Period
Body weight 
category 
(formulation)
Flexible doses for the Titration Period by study week
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
<50kg (oral 
solution)
2mg/kg/day
4mg/kg/day
6mg/kg/day
8mg/kg/day
10mg/kg/
day
12mg/kg/
day
≥50kg 
(tablets/oral 
solution)
100mg/day
200mg/day
300mg/day
400mg/day
500mg/day
600mg/day
Note: Subjects weighing ≥50kg who are unable or unwilling to swallow tablets can be dispensed LCM 
oral solution instead.
After completion of Week 1, investigators will assess whether a subject would tolerate a 
further dose increase or whether a subject should hold the Week 1 dose for a longer 
duration. This hold will be at the investigator’s discretion. The flexible LCM dosing 
over the remainder of the Titration Period is outlined in Table 7-2.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 153 of 203
Table 7-2:Flexible LCM dosing during the Titration Period
Body weight 
category 
(formulation)
Target dose 
increase/weeka
(titration)
Dose decrease per 
back-titration step
Subsequent dose increaseb
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Min
Max
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<50kg (oral 
solution)
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1mg/kg/day
2mg/kg/day
1mg/kg/day
2mg/kg/day
≥50kg 
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100mg/day
50mg/day
100mg/day
50mg/day
100mg/day
LCM=lacosamide; Max=maximum; Min=minimum
a Titration step to achieve a dose not previously administered
b Titration step subsequent to a back-titration
Note: Asymmetrical dosing with no more than 50mg difference between morning and evening doses will 
be allowed for subjects taking tablets who require back-titration in a 50mg increment (ie, only 50mg and 
100mg tablets are available)
There is no limit to the number of back-titration steps or dose holds allowed and all are 
at the investigator’s discretion; however, subjects must achieve the minimum LCM 
target dose for their body weight category by the end of the Titration Period. If it 
becomes apparent that a subject will not be able to reach the minimum target dose, then 
the subject should be withdrawn from the Titration Period and enter the Taper Period.
Subjects who have LCM titrated to a higher dose not previously administered should 
remain at that dose for ≥7 days unless a back-titration step is required based on 
tolerability. Subjects who have LCM back-titrated must remain on the lower dose for 
≥3 days (in order to reach steady state) before a subsequent dose increase. After 
back-titration, subjects who return to a higher dose previously administered must 
maintain that dose for ≥3 days before subsequent titration to a higher dose.
As outlined in Table 7-3, subjects will be required to achieve and maintain at least a 
minimum LCM dose for at least the final 3 days of Week 6 to be eligible for entry into 
the Maintenance Period. Subjects may have a back-titration step as late as the last day 
of Week 6, as long as the minimum target dose is maintained.
Table 7-3:Required LCM dose for at least the final 3 days of Week 6
Body weight category 
(formulation)
LCM for at least the final 3 days of Week 6
Minimum
Maximum
<50kg (oral solution)
4mg/kg/day
12mg/kg/day
≥50kg (tablets/oral solution)
200mg/day
600mg/day
LCM=lacosamide
Eligible subjects (those who reach and maintain at least the minimum LCM dose for at 
least the final 3 days of the Titration Period) will enter a 12-week Maintenance Period 
at the dose they achieved at the last day of Week 6. The LCM dose will remain stable 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 154 of 203
throughout the Maintenance Period. Subjects who require a change in dose during the 
Maintenance Period will be withdrawn from the study. Subjects who require a change in 
formulation during the Maintenance Period should consult the medical monitor to 
assess if the subject can continue in the study. Subjects may be eligible for participation in 
the additional open-label study (SP848) if they have completed the Maintenance Period and 
are taking a minimum dose of 4mg/kg/day for subjects weighing <50kg, and 
200mg/day (tablets/oral solution) for subjects weighing ≥50kg. Subjects will begin SP848 
on the LCM dose they were taking in the Maintenance Period in SP0966. Subjects who do 
not complete the full 12 weeks of the Maintenance Period may still be eligible to enter the 
SP848 open-label study after consultation with the medical monitor.
Subjects who choose not to participate in the open-label study or subjects who discontinue
due to other reasons will enter a 2- to 4-week Taper Period followed by a Safety 
Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM and a Safety Follow-Up 
Telephone Contact 30 days (-1/+3 days) after the final dose of LCM. The doses to be used 
during the Taper Period and the duration of the Taper Period will depend on the dose 
maintained during the Maintenance Period. 
Table 7-4 and Table 7-5 display the recommended LCM dose reductions during the 
Taper Period for subjects <50kg and ≥50kg, respectively. A slower taper is permitted if 
medically necessary. Whenever possible, these cases should be discussed with the medical 
monitor prior to withdrawing the subject from the study, especially in cases in which exit 
criteria have been met. In case of an emergency, a faster taper is permitted after discussion 
with the medical monitor, whenever possible. Taper of LCM may not be required for 
some subjects who discontinue study medication prematurely, depending on the 
treatment option selected by the investigator in consultation with the subject and/or 
parent/legal representative.
Table 7-4: Recommended LCM dose taper for subjects <50kg receiving oral solution 
formulation
Maximum LCM dose 
achieved
Taper schedule
Week 19
Week 20
Week 21
Week 22
11-12mg/kg/day
9mg/kg/day
6mg/kg/day
4mg/kg/day
2mg/kg/day
9-10mg/kg/day
8mg/kg/day
6mg/kg/day
4mg/kg/day
2mg/kg/day
7-8mg/kg/day
6mg/kg/day
4mg/kg/day
2mg/kg/day
2mg/kg/day
5-6mg/kg/day
4mg/kg/day
2mg/kg/day
2mg/kg/day
NA
3-4mg/kg/day
2mg/kg/day
2mg/kg/day
NA
NA
LCM=lacosamide; NA=not applicable (taper not required)
Note: Subjects with doses <3mg/kg/day do not need to taper. End of Taper Visit will be at the end of 
Week 22 for subjects undergoing 4 weeks of taper, at the end of Week 21 for subjects undergoing 3 weeks 
of taper, and at the end of Week 20 for subjects undergoing 2 weeks of taper.
Note: Subjects not requiring taper will enter directly into the Safety Follow-Up Period and not attend any 
Taper Period visits.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 155 of 203
Note: The study week numbers provided are for subjects who complete the Maintenance Period and enter 
the Taper Period. The study week numbers provided do not apply to subjects who enter the Taper Period 
at other times.
Table 7-5: Recommended LCM dose taper for subjects ≥50kg receiving oral solution or 
tablet formulation
Maximum LCM 
dose maintained
Taper schedule
Week 19
Week 20
Week 21
Week 22
550-600mg/day
500mg/day
300mg/day
200mg/day
100mg/day
450-500mg/day
400mg/day
300mg/day
200mg/day
100mg/day
350-400mg/day
300mg/day
200mg/day
100mg/day
100mg/day
250-300mg/day
200mg/day
100mg/day
100mg/day
NA
150-200mg/day
100mg/day
100mg/day
NA
NA
LCM=lacosamide; NA=not applicable (taper not required)
Note: Subjects with doses <150mg/day do not need to taper. End of Taper Visit will be at the end of Week 
22 for subjects undergoing 4 weeks of taper, at the end of Week 21 for subjects undergoing 3 weeks of 
taper, and at the end of Week 20 for subjects undergoing 2 weeks of taper.
Note: Subjects not requiring taper will enter directly into the Safety Follow-Up Period and not attend any 
Taper Period visits.
Note: The study week numbers provided are for subjects who complete the Maintenance Period and enter 
the Taper Period. The study week numbers provided do not apply to subjects who enter the Taper Period 
at other times.
Change #23
Section 7.5 Handling and storage requirements
Lacosamide is to be stored according to the instructions on the label. Lacosamide is stable at 
room temperature and is to be stored at temperatures not exceeding 25°C (77°F). Lacosamide 
should not be frozen.
Appropriate storage conditions must be ensured either by controlled room 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 communicated to the 
Clinical Project Manager (CPM) (or designee) before further use of the IMP.
The CPM (or designee) will transmit the out-of-range temperature (copy of the temperature 
log and duration of the out-of-range temperature, if available) to the Drug Supply 
Coordinator. Based on discussion with a UCB Quality Assurance representative, the Drug 
Supply Coordinator will then provide the CPM (or designee) with instructions for the site 
regarding use of the IMP.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 156 of 203
Has been changed to:
Lacosamide is to be stored according to the instructions on the label. Lacosamide is stable at 
room temperature and is to be stored at temperatures not exceeding 25°C (77°F). Lacosamide 
should not be refrigerated or frozen.
Appropriate storage conditions must be ensured either by controlled room temperature, or by 
completion of a temperature log (showing minimum and maximum temperatures reached 
over the time interval) in accordance with local requirements on a regular basis. Data 
should be available to support the temperature conditions maintained at the clinical site 
(eg manual temperature logs or automated chart recordings).
In case an out of range temperature is noted, it must be immediately communicated to 
the sponsor’s designee in accordance with the pharmacy manual.
Change #24
Section 7.7 Procedures for monitoring subject compliance
At each visit after IMP is dispensed, subjects must return all unused IMP and empty IMP 
containers. Drug accountability must be done in the subject’s presence in order to obtain 
explanations regarding discrepancies in compliance with the dosing regimen. Drug 
accountability must be recorded on the Drug Accountability form.
Has been changed to:
At each visit after IMP is dispensed, subjects must return all used, unused, and empty IMP
containers. Drug accountability must be done in the subject’s presence in order to obtain 
explanations regarding discrepancies in compliance with the dosing regimen. Drug 
accountability must be recorded on the Drug Accountability form.
Change #25
Section 7.8.1 Permitted and prohibited concomitant treatments (medications and 
therapies)
Subject must have been maintained on a stable dose regimen of up to 3 marketed AEDs for at 
least 4 weeks prior to Visit 1 (ie, prior to entry into the Baseline Period).
Vagal nerve stimulation is allowed and will not be counted as a concomitant AED. Vagal 
nerve stimulation (implanted for at least 6 months and stable for at least 4 weeks before 
Visit 1) must be kept stable during the Baseline Period and the Maintenance Period.
The following medications/therapies are prohibited during the course of this study:
•
Neuroleptics
•
Monoamine oxidase (MAO) inhibitors
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 157 of 203
•
Barbiturates (except as anti-epileptic medications)
•
Narcotic analgesics
Only stable use of amphetamines and sedative antihistamines is allowed during the study. 
Only stable, low doses of anxiolytics or once-daily hypnotics are allowed for non epilepsy 
indications.
Subjects who have been treated with vigabatrin and experienced any vision loss are excluded 
from the study. Subjects who have received vigabatrin in the past must have documentation 
of an assessment for vision loss prior to study entry or documentation of why visual field 
testing cannot be performed.
Subjects who have been treated with felbamate and have experienced any serious toxicity 
issues (defined as liver failure, aplastic anemia) with this treatment are excluded from the 
study. Subjects treated with felbamate for less than 12 months are also excluded. Any subject 
who has been treated with felbamate for at least 12 months and has not experienced serious 
toxicity issues is eligible for the study.
The chronic use of benzodiazepines is allowed for treatment of epilepsy. Benzodiazepines 
taken for treatment of epilepsy will be counted as 1 of the AEDs and the dose regimen must 
be stable for at least 28 days prior to Visit 1. Intermittent use of benzodiazepines as rescue 
therapy for epilepsy is allowed if taken at a maximum frequency of 1 day per month (with up 
to 3 doses within 24 hours). 
Oral contraceptive use is allowed if ethinylestradiol dosage is at least 30μg per intake 
(50μg if associated with carbamazepine or other strong enzyme inducers [eg, phenobarbital, 
primidone, oxcarbazepine]).
Therapy that becomes necessary (in the investigator’s opinion) during the course of the study 
must not be refused to a subject, even if described above as a therapy that is expressly not 
permitted. In cases where this occurs but withdrawal criteria have not been met, the 
advisability of the subject’s continuation in the study must be discussed between the medical 
monitor and the investigator.
Has been changed to:
Subject must have been maintained on a stable dose regimen of 1 to 3 marketed AEDs for at 
least 4 weeks prior to Visit 1 (ie, prior to entry into the Baseline Period); the dose regimen 
of the AEDs must be kept stable through the end of the Maintenance Period.
Vagal nerve stimulation is allowed and will not be counted as a concomitant AED. The VNS 
device must be implanted for at least 6 months before Visit 1, and the device settings 
must be stable for at least 4 weeks before Visit 1 and be kept stable during the Baseline 
Period and through the end of the Maintenance Period.
The following medications/therapies are prohibited during the course of this study:
•
Neuroleptics
•
MAO inhibitors
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 158 of 203
•
Barbiturates (except as anti-epileptic medications)
•
Narcotic analgesics
Subjects who have been treated with vigabatrin and experienced any vision loss are excluded 
from the study. Subjects who have received vigabatrin in the past must have documentation 
of an assessment for vision loss prior to study entry or documentation of why visual field 
testing cannot be performed.
Subjects who have been treated with felbamate and have experienced any serious toxicity 
issues (defined as liver failure, aplastic anemia) with this treatment are excluded from the 
study. Subjects treated with felbamate for less than 12 months are also excluded. Any subject 
who has been treated with felbamate for at least 12 months and has not experienced serious 
toxicity issues is eligible for the study.
The following medications are not allowed unless used as described:
•
Amphetamines and sedative antihistamines: stable use only.
•
Anxiolytics or once-daily hypnotics: stable, low doses are allowed for nonepilepsy 
indications only.
The chronic use of benzodiazepines is allowed for treatment of epilepsy. 
Benzodiazepines taken for treatment of epilepsy will be counted as 1 of the AEDs, and 
the dose regimen must be stable for ≥28 days prior to Visit 1. Intermittent use of 
benzodiazepines as rescue therapy for epilepsy is allowed if taken at a maximum 
frequency of 1 day per week (with up to 3 doses within 24 hours).
Therapy that becomes necessary (in the investigator’s opinion) during the course of the 
study must not be refused to a subject, even if described above as a therapy that is 
expressly not permitted. In cases where this occurs but withdrawal criteria have not 
been met, the advisability of the subject’s continuation in the study must be discussed 
between the medical monitor and the investigator.
Change #26
Section 7.8.2 Rescue medication
The use of benzodiazepines as rescue therapy for epilepsy is allowed if taken at a maximum 
frequency of 1 day per month (with up to 3 doses within 24 hours) during study participation; 
more frequent use precludes subjects from study participation.
Has been changed to:
The use of benzodiazepines as rescue therapy for epilepsy is allowed if taken at a maximum 
frequency of 1 day per week (with up to 3 doses within 24 hours) during study participation; 
more frequent use precludes subjects from study participation.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 159 of 203
Change #27
Section 8.1.1 Visit 1 (Week -6) Screening Visit
At Visit 1, subjects will be evaluated for their suitability for enrollment. The Screening Visit 
assessments will be conducted 6 weeks prior to the first administration of LCM. It is 
acceptable for the Screening assessments to be conducted over >1 day, although it should not 
extend over a period longer than 1 week. Prior to the conduct of any study-related 
procedures, a complete explanation (both verbal and written) of the nature and purpose of the 
study will be given to the subject (when possible or as required according to local IRBs/IECs) 
and the subject’s parent/legal guardian by the investigator (or designee). The subject’s 
parent/legal guardian will be requested to sign and date the IRB/IEC-approved ICF. When 
possible, or as required by the local IRB/IEC, the subject will be requested to give assent to 
participate in the study.
The subject’s eligibility for the study will be determined on the basis of the 
inclusion/exclusion criteria, signature of an ICF prior to any study-related procedures or 
evaluations, and the results of the following pretreatment assessments (for further details of 
the assessments and the required procedures and methods, please refer to Section 9 and 
Section 11 of this protocol):
•
Contact IXRS to obtain unique subject identification number.
•
Review seizure history. The subject or caregiver (including parent/legal guardian) will be 
asked how many seizures the subject has had over the past 4 weeks as a historical 
Baseline.
•
Concomitant AED(s) assessment.
•
Changes in VNS settings.
•
Concomitant medication(s) assessment.
•
Medical history assessment.
•
Complete physical examination.
•
Complete neurological examination.
•
12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to 
vital signs assessment and collection of blood samples, and, if possible, with the subject 
in the supine position for 5 minutes preceding the ECG recordings).
•
Vital signs (BP and pulse, including orthostatic assessments).
•
Body weight and height assessment.
•
Epilepsy surgery assessment.
•
C-SSRS (if applicable). The C-SSRS will be completed for all subjects ≥6 years of age.
•
Blood sample for clinical chemistry, hematology, and endocrinology.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 160 of 203
•
Serum pregnancy test (if applicable).
•
Urine sample for urinalysis (if applicable). Will be performed for subjects aged 5 to 
17 years.
•
Tanner Stage (if applicable). The Tanner Stage will be performed only for subjects who 
are pubescent at Visit 1 or who will enter puberty during the course of the study.
•
Dispense subject diary.
•
AE reporting.
•
Health care resource use.
Eligible subjects will be scheduled to return to the clinic (Visit 2, Week 0) approximately 
6 weeks ±2 days after the Screening Visit.
Has been changed to:
At Visit 1, subjects will be evaluated for their suitability for enrollment. The Screening Visit 
assessments will be conducted 6 weeks prior to the first administration of LCM. It is 
acceptable for the Screening assessments to be conducted over >1 day. Prior to the conduct of 
any study-related procedures, a complete explanation (both verbal and written) of the nature 
and purpose of the study will be given to the subject (when possible or as required according 
to local IRBs/IECs) and the subject’s parent/legal representative by the investigator (or 
designee). The subject’s parent/legal representative will be requested to sign and date the 
IRB/IEC-approved ICF. When possible, or as required by the local IRB/IEC, the subject will 
be requested to give assent to participate in the study.
The subject’s eligibility for the study will be determined on the basis of the 
inclusion/exclusion criteria, signature on an ICF prior to any study-related procedures or 
evaluations, and the results of the following pretreatment assessments (for further details of 
the assessments and the required procedures and methods, please refer to Section 9 and 
Section 11 of this protocol):
•
Contact IXRS to obtain unique subject identification number.
•
Review seizure history. The subject or caregiver (including parent/legal representative) 
will be asked how many seizures the subject has had over the past 4 weeks as a historical 
Baseline.
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Medical history assessment.
•
Complete physical examination.
•
Complete neurological examination.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 161 of 203
•
12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed 
prior to any blood draws and vital signs assessment and, if possible, with the subject 
in the supine position for approximately 5 minutes preceding the recordings and 
during the recordings).
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory 
subjects).
•
Body weight and height assessment.
•
Head circumference.
•
Epilepsy surgery assessment.
•
C-SSRS (if applicable). The C-SSRS will be completed for all subjects ≥6 years of age.
•
Blood sample for clinical chemistry, hematology, and endocrinology.
•
Serum pregnancy test (if applicable).
•
Urine sample for urinalysis (if applicable). Will be performed for subjects aged 5 to 
17 years.
•
Tanner Stage (if applicable). The Tanner Stage will be performed only for subjects who 
are pubescent at Visit 1 or who will enter puberty during the course of the study.
•
Dispense subject diary and remind subject to complete subject diary on a daily basis.
•
AE reporting.
Eligible subjects will be scheduled to return to the clinic (Visit 2, Day 1) approximately 
6 weeks ±2 days after the Screening Visit.
Change #28
Section 8.1.2 Telephone contact (Week -3)
Three weeks before Visit 2, the investigator or designee should contact the subject’s 
caregiver (including parent/legal guardian) by telephone. The investigator (or designee) 
should remind the subject’s caregiver (including parent/legal guardian) to ensure the diary is 
completed. The following should be performed via telephone:
•
Review inclusion/exclusion criteria
•
Concomitant medications assessment
•
Concomitant AEDs assessment
•
Subject diary review
•
Review withdrawal criteria
•
AE reporting
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 162 of 203
Has been changed to:
Three weeks before Visit 2 (±2 days), the investigator or designee should contact the 
subject’s caregiver (including parent/legal representative) by telephone. The investigator (or 
designee) should remind the subject’s caregiver (including parent/legal representative) to 
ensure the diary is completed. The following should be performed via telephone:
•
Review inclusion/exclusion criteria
•
Concomitant medications assessment
•
Concomitant AEDs assessment
•
Reminder to complete subject diary on a daily basis 
•
Review withdrawal criteria
•
AE reporting
Change #29
Section 8.1.3 Visit 2 (Week 0)
Subjects will be asked to return to the clinic on the morning of the day prior to Visit 2 (end of 
Week 0) to begin 24-hour ambulatory EEG recordings. Scalp electrodes will be attached, and 
subjects will receive a recording device. Subjects will be asked to return approximately 
24 hours later (for Visit 2) for removal of the scalp electrodes and return of the recording 
device. At Visit 2 (end of Week 0), the investigator should determine whether the subject is 
still eligible and willing to continue in the study. 
The following will be performed prior to the first dose of LCM:
•
Review inclusion/exclusion criteria.
•
Concomitant AED(s) assessment.
•
Changes in VNS settings.
•
Concomitant medication(s) assessment.
•
Complete physical examination.
•
Complete neurological examination.
•
12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to 
vital signs assessment and collection of blood samples, and, if possible, with the subject 
in the supine position for 5 minutes preceding the ECG recordings. Recordings should be 
performed at least 15 minutes after removal of scalp electrodes used for the 24-hour 
ambulatory EEG recording).
•
Vital signs (BP and pulse, including orthostatic assessments).
•
Body weight and height assessment.
•
C-SSRS (if applicable).
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 163 of 203
•
Blood sample for clinical chemistry and hematology.
•
Blood sample for LCM and concomitant AED plasma concentrations (before dosing with 
LCM). Blood sample will be drawn along with clinical chemistry and hematology 
samples.
•
Achenbach CBCL (if applicable); CBCL/1½-5 or CBCL/6-18 for pediatric subjects 
≥18 months of age.
•
Bayley Scales of Infant and Toddler Development®, Third Edition (Bayley-III Scales) (if 
applicable). For pediatric subjects <18 months of age at Baseline enrolled in 
English-speaking countries. 
•
BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) (version consistent with 
age at the visit).
•
PedsQL for subjects ≥1 month to ≤18 years of age (version consistent with age at the 
visit).
•
Urine sample for urinalysis (if applicable).
•
Urine pregnancy test (if applicable).
•
Subject diary return/review.
•
AE reporting.
•
Review withdrawal criteria.
•
Contact IXRS to obtain bottle number(s).
•
Dispense subject diary.
•
Health care resource use.
•
Dispense LCM. Subjects should take the first dose of LCM based on body weight in the 
clinic. The starting dose for subjects taking the oral solution formulation will be either 
2mg/kg/day or 3mg/kg/day, and the starting dose for subjects taking the tablet 
formulation will be 100mg/day.
Has been changed to:
Section 8.2.1 Visit 2 (Day 1)
Subjects will be asked to return to the clinic on the morning of the day prior to Visit 2 (end of 
Week 0) to begin 24-hour ambulatory EEG recordings. Scalp electrodes will be attached, and 
subjects will receive a recording device. Subjects will be asked to return approximately 
24 hours later (for Visit 2, Day 1) for removal of the scalp electrodes and return of the 
recording device. At Visit 2, the investigator should determine whether the subject is still 
eligible and willing to continue in the study. 
The following will be performed prior to the first dose of LCM:
•
Review inclusion/exclusion criteria.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 164 of 203
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Complete physical examination.
•
Complete neurological examination.
•
12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed 
prior to any blood draws and vital signs assessment and, if possible, with the subject 
in the supine position for approximately 5 minutes preceding the recordings and 
during the recordings. Recordings should be performed at least 15 minutes after 
removal of scalp electrodes used for the 24-hour ambulatory EEG recording).
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory 
subjects).
•
Body weight and height assessment.
•
C-SSRS (if applicable).
•
Blood sample for clinical chemistry and hematology.
•
Blood sample for LCM and concomitant AED plasma concentrations (before dosing with 
LCM). Blood sample will be drawn along with clinical chemistry and hematology 
samples.
•
Achenbach CBCL (if applicable); CBCL/1½-5 or CBCL/6-18 for pediatric subjects 
≥18 months of age.
•
Bayley Scales of Infant and Toddler Development®, Third Edition (Bayley-III Scales) (if 
applicable). For pediatric subjects <18 months of age at Baseline enrolled in 
English-speaking countries. 
•
BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) (version consistent with 
age at the visit).
•
PedsQL for subjects ≥1 month to ≤18 years of age (version consistent with age at the 
visit).
•
Urine sample for urinalysis (if applicable).
•
Urine pregnancy test (if applicable).
•
Subject diary return/review.
•
AE reporting.
•
Review withdrawal criteria.
•
Contact IXRS.
•
Dispense subject diary.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 165 of 203
•
Reminder to complete subject diary on a daily basis.
•
Health care resource use.
•
Dispense LCM. Subjects should take the first dose of LCM (based on body weight) in the 
clinic. The starting dose for subjects taking the oral solution formulation will be 
2mg/kg/day, and the starting dose for subjects taking the tablet formulation will be 
100mg/day.
Change #30
The following section has been added:
Section 8.2.2 Telephone contacts (Weeks 1 and 3)
At the end of Weeks 1 and 3 (±2 days), the investigator or designee should contact the 
subject’s caregiver (including parent/legal representative) by telephone. The 
assessments for these telephone contacts are the same as those performed during the 
telephone contact at Week -3 in Section 8.1.2 with the exception that inclusion/exclusion 
criteria do not need to be checked at Weeks 1 and 3.
Change #31
Section 8.2.1 Visit 3 (Week 1)
At Visit 3 (end of Week 1), subjects will return for a clinic visit, and the following will be 
performed:
•
Concomitant AED(s) assessment.
•
Changes in VNS settings.
•
Concomitant medication(s) assessment.
•
Brief physical examination.
•
Brief neurological examination.
•
Vital signs (BP and pulse, including orthostatic assessments).
•
Body weight assessment.
•
C-SSRS (if applicable).
•
12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to 
vital signs assessment and collection of blood samples, and, if possible, with the subject 
in the supine position for 5 minutes preceding the ECG recordings).
•
Subject diary return/review.
•
LCM return.
•
AE reporting.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 166 of 203
•
Review withdrawal criteria.
•
Contact IXRS to obtain bottle number(s).
•
Dispense subject diary.
•
Health care resource use.
•
Dispense LCM. The subject’s LCM dose can be titrated based on body weight to either 
4mg/kg/day or 6mg/kg/day (oral solution) or 200mg/day (tablets), if clinically 
appropriate.
Has been changed to:
Section 8.2.3 Visit 3 (Week 2)
At Visit 3 (end of Week 2 ±2 days), subjects will return for a clinic visit, and the following 
will be performed:
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory 
subjects).
•
Body weight assessment.
•
Urine pregnancy test (if applicable).
•
C-SSRS (if applicable).
•
12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed 
prior to any blood draws and vital signs assessment and, if possible, with the subject 
in the supine position for approximately 5 minutes preceding the recordings and 
during the recordings).
•
Subject diary return/review.
•
LCM return.
•
AE reporting.
•
Review withdrawal criteria.
•
Contact IXRS.
•
Dispense subject diary.
•
Reminder to complete subject diary on a daily basis.
•
Health care resource use.
•
Dispense LCM. 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 167 of 203
Change #32
Section 8.2.2 Visit 4 (Week 2)
Assessments for Visit 4 (end of Week 2) are the same as those described for Visit 3 (end of 
Week 1) in Section 8.2.1, with the following additions: 
•
A blood sample for clinical chemistry and hematology
•
A urine sample for urinalysis (if applicable) 
The subject’s LCM dose can be titrated based on body weight to either 6mg/kg/day or 
9mg/kg/day (oral solution) or 300mg/day (tablets), if clinically appropriate.
Has been changed to:
Section 8.2.4 Visit 4 (Week 4)
Assessments for Visit 4 (end of Week 4 ±2 days) are the same as those described for Visit 3 
(end of Week 2) in Section 8.2.3. This visit is optional and will only be required if a 
subject requires further LCM dose adjustment.
Change #33
Section 8.2.3 Visit 5 (Week 3)
Assessments for Visit 5 (end of Week 3) are the same as those described for Visit 3 (end of 
Week 1) in Section 8.2.1.
The subject’s LCM dose can be titrated based on body weight to either 8mg/kg/day or 
12mg/kg/day (oral solution) or 400mg/day (tablets), if clinically appropriate.
Has been changed to:
Section 8.2.5 Visit 5 (Week 5)
Assessments for Visit 5 (end of Week 5 ±2 days) are the same as those described for Visit 3 
(end of Week 2) in Section 8.2.3. This visit is optional and will only be required if a 
subject requires further LCM dose adjustment.
Change #34
Section 8.2.4 Visit 6 (Week 4)
Subjects will be asked to return to the clinic on the morning of the day prior to Visit 6 (end of 
Week 4) to begin 24-hour ambulatory EEG recordings. Scalp electrodes will be attached, and 
subjects will receive a recording device. Subjects will be asked to return approximately 
24 hours later (for Visit 6) for removal of the scalp electrodes and return of the recording 
device.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 168 of 203
At Visit 6 (end of Week 4), subjects will return for a clinic visit, and the following will be 
performed:
•
Concomitant AED(s) assessment.
•
Changes in VNS settings.
•
Concomitant medication(s) assessment.
•
Brief physical examination.
•
Brief neurological examination.
•
12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to 
vital signs assessment and collection of blood samples, and, if possible, with the subject 
in the supine position for 5 minutes preceding the ECG recordings. Recordings should be 
performed at least 15 minutes after removal of scalp electrodes used for the 24-hour 
ambulatory EEG recording). 
•
Vital signs (BP and pulse, including orthostatic assessments).
•
Body weight assessment.
•
C-SSRS (if applicable).
•
Blood sample for clinical chemistry and hematology.
•
Blood sample for LCM and concomitant AED plasma concentrations (at any time 
post-dosing with LCM). Blood sample will be drawn along with clinical chemistry and 
hematology samples.
•
Urine sample for urinalysis (if applicable).
•
Urine pregnancy test (if applicable).
•
Achenbach CBCL (if applicable); CBCL/1½-5 or CBCL/6-18 for pediatric subjects 
≥18 months of age.
•
Subject diary return/review.
•
LCM return.
•
AE reporting.
•
Review withdrawal criteria.
•
Contact IXRS to obtain bottle number(s).
•
Dispense subject diary.
•
Health care resource use.
•
Dispense LCM. 
Has been changed to:
Section 8.2.6 Visit 6 (Week 6, End of Titration)
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 169 of 203
Subjects will be asked to return to the clinic on the morning of the day prior to Visit 6 (end of 
Week 6 ±2 days) to begin 24-hour ambulatory EEG recordings. Scalp electrodes will be 
attached, and subjects will receive a recording device. Subjects will be asked to return 
approximately 24 hours later (for Visit 6) for removal of the scalp electrodes and return of the 
recording device.
At Visit 6 (end of Week 6), subjects will return for a clinic visit, and the following will be 
performed:
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Brief physical examination.
•
Brief neurological examination.
•
12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed 
prior to any blood draws and vital signs assessment and, if possible, with the subject 
in the supine position for approximately 5 minutes preceding the recordings and 
during the recordings. Recordings should be performed at least 15 minutes after 
removal of scalp electrodes used for the 24-hour ambulatory EEG recording). 
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory 
subjects).
•
Body weight assessment.
•
C-SSRS (if applicable).
•
Blood sample for clinical chemistry and hematology.
•
Urine sample for urinalysis (if applicable).
•
Urine pregnancy test (if applicable).
•
Achenbach CBCL (if applicable); CBCL/1½-5 or CBCL/6-18 for pediatric subjects 
≥18 months of age (same version that was used at Visit 2).
•
Subject diary return/review.
•
LCM return.
•
AE reporting.
•
Review withdrawal criteria.
•
Contact IXRS.
•
Dispense subject diary.
•
Reminder to complete subject diary on a daily basis.
•
Health care resource use.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 170 of 203
•
Dispense LCM for the first 4 weeks of the Maintenance Period.
Change #35
Section 8.3.1 Telephone contacts (Weeks 6, 10, and 14)
At the end of Weeks 6, 10, and 14, the investigator or designee should contact the subject’s 
caregiver (including parent/legal guardian) by telephone. The assessments for these telephone 
contacts are the same as those performed during the telephone contact at Week -3 in Section 
8.1.2 with the exception that inclusion/exclusion criteria do not need to be checked at 
Weeks 6, 10, and 14.
Subjects must titrate to at least 6mg/kg/day for subjects weighing ≤30kg, 4mg/kg/day for 
subjects weighing >30kg to ≤50kg, or 200mg/day (tablets/oral solution) for subjects weighing 
>50kg in order to enter the Maintenance Period.
Has been changed to:
Section 8.3.1 Telephone contacts (Weeks 8, 12, and 16)
At the end of Weeks 8, 12, and 16 (±2 days), the investigator or designee should contact the 
subject’s caregiver (including parent/legal representative) by telephone. The assessments for 
these telephone contacts are the same as those performed during the telephone contact at 
Week -3 in Section 8.1.2 with the exception that inclusion/exclusion criteria do not need to be 
checked at Weeks 8, 12, and 16.
Subjects must titrate to at least 4mg/kg/day for subjects weighing <50kg, or 
200mg/day (tablets/oral solution) for subjects weighing ≥50kg in order to enter the 
Maintenance Period.
Change #36
Section 8.3.2 Visit 7 (Week 8)
At Visit 7 (end of Week 8), subjects will return for a clinic visit, and the following will be 
performed:
•
Concomitant AED(s) assessment.
•
Changes in VNS settings.
•
Concomitant medication(s) assessment.
•
Brief physical examination.
•
Brief neurological examination.
•
Vital signs (BP and pulse, including orthostatic assessments).
•
Body weight assessment.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 171 of 203
•
12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to 
vital signs assessment and collection of blood samples, and, if possible, with the subject 
in the supine position for 5 minutes preceding the ECG recordings).
•
C-SSRS (if applicable).
•
Blood sample for clinical chemistry and hematology.
•
Urine sample for urinalysis (if applicable).
•
Urine pregnancy test (if applicable).
•
Subject diary return/review.
•
LCM return.
•
AE reporting.
•
Review withdrawal criteria.
•
Contact IXRS to obtain bottle number(s).
•
Dispense subject diary.
•
Health care resource use.
•
Dispense LCM.
Has been changed to:
Section 8.3.2 Visit 7 (Week 10)
At Visit 7 (end of Week 10 ±2 days), subjects will return for a clinic visit, and the following 
will be performed:
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory 
subjects).
•
Body weight assessment.
•
12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed 
prior to any blood draws and vital signs assessment and, if possible, with the subject 
in the supine position for approximately 5 minutes preceding the recordings and 
during the recordings).
•
C-SSRS (if applicable).
•
Blood sample for clinical chemistry and hematology.
•
Urine pregnancy test (if applicable).
•
Subject diary return/review.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 172 of 203
•
LCM return.
•
AE reporting.
•
Review withdrawal criteria.
•
Contact IXRS.
•
Dispense subject diary.
•
Reminder to complete subject diary on a daily basis.
•
Health care resource use.
•
Dispense LCM.
Change #37
Section 8.3.3 Visit 8 (Week 12)
Assessments for Visit 8 (end of Week 12) are the same as those described for Visit 7 (end of 
Week 8) in Section 8.3.2 with the exception of there being no urinalysis assessment at 
Visit 8. 
Has been changed to:
Section 8.3.3 Visit 8 (Week 14)
Assessments for Visit 8 (end of Week 14 ±2 days) are the same as those described for Visit 7 
(end of Week 10) in Section 8.3.2 with the addition of:
•
Brief physical examination.
•
Brief neurological examination.
For the assessment of clinical chemistry and hematology, if no abnormality is observed 
in the laboratory blood samples from the previous visit, the assessment does not have to 
be performed.
Change #38
Section 8.3.4 Visit 9 (Week 16)/Early Termination Visit
Subjects will be asked to return to the clinic on the morning of the day prior to Visit 9 (end of 
Week 16)/Early Termination to begin 24-hour ambulatory EEG recordings. Scalp electrodes 
will be attached, and subjects will receive a recording device. Subjects will be asked to return 
approximately 24 hours later (for Visit 9/Early Termination Visit) for removal of the scalp 
electrodes and return of the recording device.
At Visit 9 (end of Week 16) or the Early Termination Visit (if applicable), subjects will 
return for a clinic visit, and the following will be performed:
•
Concomitant AED(s) assessment.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 173 of 203
•
Changes in VNS settings.
•
Concomitant medication(s) assessment.
•
Complete physical examination.
•
Complete neurological examination.
•
12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to 
vital signs assessment and collection of blood samples, and, if possible, with the subject 
in the supine position for 5 minutes preceding the ECG recordings. Recordings should be 
performed at least 15 minutes after removal of scalp electrodes used for the 24-hour 
ambulatory EEG recording).
•
Vital signs (BP and pulse, including orthostatic assessments).
•
Body weight and height assessment.
•
C-SSRS (if applicable).
•
Blood sample for clinical chemistry, hematology, and endocrinology.
•
Blood sample for LCM and concomitant AED plasma concentrations (at any time 
post-dosing with LCM). Blood sample will be drawn along with clinical chemistry and 
hematology samples.
•
Urine sample for urinalysis (if applicable).
•
Serum pregnancy test (if applicable).
•
Clinical Global Impression of Change assessment.
•
Caregiver’s Global Impression of Change assessment.
•
Achenbach CBCL (if applicable); CBCL/1½-5 or CBCL/6-18 for pediatric subjects 
≥18 months of age.
•
BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) (version consistent with 
age at Visit 2).
•
PedsQL for subjects ≥1 month to ≤18 years of age (version consistent with age at Visit 2).
•
Tanner Stage (if applicable). The Tanner Stage will be performed only for subjects who 
are pubescent at Visit 1 or who will enter puberty during the course of the study.
•
Subject diary return/review.
•
LCM return.
•
AE reporting.
•
Review withdrawal criteria.
•
Contact IXRS to obtain bottle number(s).
•
Dispense subject diary (for subjects entering Taper Period and not SP848).
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 174 of 203
•
Health care resource use.
•
Dispense LCM (for subjects entering Taper Period and not SP848). 
Subjects may be eligible for participation in the open-label study (SP848) if they have been 
maintained on a dose of at least 6mg/kg/day (oral solution) for subjects weighing ≤30kg, 
4mg/kg/day (oral solution) for subjects weighing >30kg to ≤50kg, and 
200mg/day (tablets/oral solution) in subjects weighing >50kg in the Maintenance Period. 
Subjects will begin SP848 on the LCM dose they were taking in the Maintenance Period in 
SP0966.
Subjects who choose not to participate in the open-label study, subjects who are only able to 
tolerate the lowest LCM dose (100mg/day for the tablet formulation, 3mg/kg/day or 
2mg/kg/day for the oral solution formulation), or subjects discontinuing due to other reasons 
will enter up to a 4-week Taper Period followed by a 1-week study drug-free Safety Period 
and Final Safety telephone contact.
Has been changed to:
Section 8.3.4 Visit 9 (Week 18)/Early Termination Visit
Subjects will be asked to return to the clinic on the morning of the day prior to Visit 9 (end of 
Week 18 ±2 days)/Early Termination to begin 24-hour ambulatory EEG recordings. Scalp 
electrodes will be attached, and subjects will receive a recording device. Subjects will be 
asked to return approximately 24 hours later (for Visit 9/Early Termination Visit) for removal 
of the scalp electrodes and return of the recording device.
At Visit 9 (end of Week 18) or the Early Termination Visit (if applicable), subjects will 
return for a clinic visit, and the following will be performed:
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Complete physical examination.
•
Complete neurological examination.
•
12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed 
prior to any blood draws and vital signs assessment and, if possible, with the subject 
in the supine position for approximately 5 minutes preceding the recordings and 
during the recordings. Recordings should be performed at least 15 minutes after 
removal of scalp electrodes used for the 24-hour ambulatory EEG recording).
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory 
subjects).
•
Body weight and height assessment.
•
Head circumference.
•
C-SSRS (if applicable).
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 175 of 203
•
Blood sample for clinical chemistry, hematology, and endocrinology.
•
Blood sample for LCM and concomitant AED plasma concentrations (at any time 
post-dosing with LCM). Blood sample will be drawn along with clinical chemistry and 
hematology samples.
•
Urine sample for urinalysis (if applicable).
•
Serum pregnancy test (if applicable).
•
Clinical Global Impression of Change assessment.
•
Caregiver’s Global Impression of Change assessment.
•
Achenbach CBCL (if applicable); CBCL/1½-5 or CBCL/6-18 for pediatric subjects 
≥18 months of age (same version that was used at Visit 2).
•
BRIEF-P (≥2 years to <5 years of age)/BRIEF (≥5 years of age) (same version that was 
used at Visit 2).
•
PedsQL for subjects ≥1 month to ≤18 years of age (same version that was used at 
Visit 2).
•
Tanner Stage (if applicable). The Tanner Stage will be performed only for subjects who 
are pubescent at Visit 1 or who will enter puberty during the course of the study.
•
Subject diary return/review.
•
LCM return.
•
AE reporting.
•
Review withdrawal criteria.
•
Contact IXRS.
•
Dispense subject diary (for subjects entering Taper Period and not SP848).
•
Reminder to complete subject diary on a daily basis (if applicable).
•
Health care resource use.
•
Dispense LCM (for subjects entering Taper Period and not SP848). 
Subjects may be eligible for participation in the open-label study (SP848) if they have been 
maintained on a dose of at least 4mg/kg/day (oral solution) for subjects weighing <50kg, 
or 200mg/day (tablets/oral solution) for subjects weighing ≥50kg in the Maintenance 
Period. Subjects will begin SP848 on the LCM dose they were taking in the Maintenance 
Period in SP0966.
Subjects who choose not to participate in the open-label study or subjects who 
discontinue due to other reasons will enter a 2- to 4-week Taper Period followed by a 
Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM and a Safety 
Follow-Up Telephone Contact 30 days (-1/+3 days) after the final dose of LCM.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 176 of 203
Investigators should discuss treatment options with the subject and/or his/her
parent/legal representative to best manage the subject’s epilepsy. Taper of LCM may 
not be required for some subjects who discontinue study medication prematurely, 
depending on the treatment option selected by the investigator in consultation with the 
subject and/or parent/legal representative. These subjects should complete Visit 9/Early 
Termination Visit and then complete the Safety Follow-Up Visit 2 weeks (±2 days) after 
the final dose of LCM and a Safety Follow-Up Telephone Contact 30 days (-1/+3 days) 
after the final dose of LCM. The End of Taper Visit is not required for subjects who 
complete or withdraw from the study and who do not undergo taper of LCM.
Change #39
Section 8.4 End of Study Period
The following paragraph has been added:
For subjects who enter the open-label study (SP848), the end of the study will be the 
date of the subject’s last assessment in SP0966 (end of Maintenance Period or Early 
Termination Visit). Subjects who do not enroll in SP848 will enter a Taper Period 
followed by a Safety Follow-Up Period as described below, and the end of the study will 
be the date of the last Safety Follow-Up Telephone Contact.
Change #40
Section 8.4.1 Taper Period (Weeks 17 to 20)/End of Taper Visit
For subjects who do not enroll in the open-label study (SP848), a Taper Period will be 
scheduled. For subjects completing the full duration of the Maintenance Period, the Taper 
Period will begin at Week 17. For subjects who do not complete the full duration of the 
Maintenance Period, the Taper Period will begin earlier, at the time that they end the 
Maintenance Period. Please refer to Section 7.2 for details of the taper schedule. 
The following will be performed at the End of Taper Visit at the end of the last week of the 
Taper Period:
•
Concomitant AED(s) assessment.
•
Changes in VNS settings.
•
Concomitant medication(s) assessment.
•
Brief physical examination.
•
Brief neurological examination.
•
Vital signs (BP and pulse, including orthostatic assessments).
•
Body weight assessment.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 177 of 203
•
12-lead ECG (2 interpretable recordings approximately 20 to 30 minutes apart prior to 
vital signs assessment and collection of blood samples, and, if possible, with the subject 
in the supine position for 5 minutes preceding the ECG recordings).
•
C-SSRS (if applicable).
•
Blood sample for clinical chemistry, hematology, and endocrinology. If no abnormality is 
observed in the laboratory blood samples from the previous visit, the End of Taper 
assessment does not have to be performed.
•
Urine sample for urinalysis (if applicable). If no abnormality is observed in the 2 previous 
urinalysis tests, the End of Taper assessment does not need to be performed. 
•
Serum pregnancy test (if applicable).
•
Subject diary return/review.
•
LCM return.
•
AE reporting.
•
Health care resource use.
Has been changed to:
Section 8.4.1 Taper Period
For subjects who do not enroll in the open-label study (SP848), a 2- to 4-week (depending 
on dose achieved) Taper Period will be scheduled. For subjects completing the full duration 
of the Maintenance Period, the Taper Period will begin at Week 19 (±2 days). For subjects 
who do not complete the full duration of the Maintenance Period, the Taper Period will begin 
earlier, at the time that they end the Maintenance Period. Please refer to Section 7.2 for 
details of the taper schedule. Taper of LCM may not be required for some subjects who 
discontinue study medication prematurely, depending on the treatment option selected 
by the investigator in consultation with the subject and/or parent/legal representative. 
These subjects should complete Visit 9/Early Termination Visit and then complete the 
Safety Follow-Up Visit 2 weeks (±2 days) after the final dose of LCM and a Safety 
Follow-Up Telephone Contact 30 days (-1/+3 days) after the final dose of LCM.
Section 8.4.1.1 Telephone Contact (Week 19)
At the end of Week 19 (±2 days) during the first week of the Taper Period, the 
investigator or designee should contact the subject’s caregiver (including parent/legal 
representative) by telephone. The following assessments will be performed:
•
Concomitant AED(s) assessment
•
Concomitant medication(s) assessment
•
Reminder to complete subject diary on a daily basis
•
AE reporting
•
Review withdrawal criteria
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 178 of 203
If any AEs necessitate a subject’s withdrawal from the study, the subject should return 
for a clinic visit as soon as possible after the occurrence of the AE.
Section 8.4.1.2 End of Taper Visit (Weeks 20 to 22)
The End of Taper Visit is not required for subjects who complete or withdraw from the 
study and who do not undergo taper of LCM. Each subject will have only 1 Taper Visit. 
The Taper Visit will be scheduled at the end of the Taper Period (Week 20, Week 21, or 
Week 22, depending on dose level achieved; see Table 7-4 and Table 7-5). A time 
window of ±2 days relative to Visit 2 (Titration Period) is applicable.
The following will be performed at the End of Taper Visit at the end of the last week of 
the Taper Period:
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Brief physical examination.
•
Brief neurological examination.
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory 
subjects).
•
Body weight assessment.
•
12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed 
prior to any blood draws and vital signs assessment and, if possible, with the subject 
in the supine position for approximately 5 minutes preceding the recordings and 
during the recordings).
•
C-SSRS (if applicable).
•
Blood sample for clinical chemistry, hematology and endocrinology. 
•
Urine sample for urinalysis (if applicable). 
•
Serum pregnancy test (if applicable).
•
Subject diary return/review.
•
LCM return.
•
AE reporting.
•
Review withdrawal criteria.
•
Contact IXRS.
•
Health care resource use.
Section 8.4.2 Safety Follow-up
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 179 of 203
Safety Follow-up is required only for subjects who do not enroll in the open-label study 
(SP848). 
Section 8.4.2.1 Safety Follow-Up Visit (Weeks 22 to 24)
The Safety Follow-Up Visit will occur 2 weeks (±2 days) after the final dose of LCM. 
The following assessments will be performed:
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Complete physical examination.
•
Complete neurological examination.
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory 
subjects).
•
Body weight and height assessment.
•
12-lead ECG (2 interpretable recordings [20 to 30 minutes apart] to be performed 
prior to any blood draws and vital signs assessment and, if possible, with the subject 
in the supine position for approximately 5 minutes preceding the recordings and 
during the recordings) (only for subjects with an abnormal reading at the previous 
visit).
•
C-SSRS (if applicable).
•
Blood sample for clinical chemistry, hematology and endocrinology (only for 
subjects with an abnormal value at the previous visit). 
•
Urine sample for urinalysis (if applicable) (only for subjects with an abnormal value 
at the previous visit). 
•
Urine pregnancy test (if applicable) (only if blood is not collected for another 
assessment).
•
AE reporting.
•
Health care resource use.
Section 8.4.2.2 Safety Follow-Up Telephone Contact (Weeks 24 to 26)
The Safety Follow-Up Telephone Contact will occur 30 days (-1/+3 days) after the final 
dose of LCM and will include the following assessments:
•
Concomitant AED(s) assessment
•
Concomitant medication(s) assessment
•
AE reporting
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 180 of 203
Change #41
Section 8.5 Unscheduled Visit
Unscheduled Visits may be performed at any time after Visit 1, at the discretion of the 
investigator. During an Unscheduled Visit, the following assessments are required: 
•
Concomitant AED(s) assessment.
•
Changes in VNS settings
•
Concomitant medication(s) assessment
•
Vital signs (BP and pulse, including orthostatic assessments)
•
Body weight assessment (height is not required)
•
Contact IXRS to obtain bottle number(s)
•
Subject diary return/review
•
AE reporting
•
Review withdrawal criteria
•
Health care resource use
If the Unscheduled Visit is due to an AE, then the C-SSRS is required.
In addition to the required assessments listed above, further assessments can be completed as 
needed and may include ECG, laboratory tests, physical examination, neurological 
examination, etc.
Has been changed to:
Unscheduled Visits may be performed at any time after Visit 1, at the discretion of the 
investigator. During an Unscheduled Visit, the following assessments are required: 
•
Concomitant AED(s) assessment.
•
VNS assessment (for subjects with an implanted VNS device).
•
Concomitant medication(s) assessment.
•
Vital signs (BP and pulse rate, including orthostatic assessments in ambulatory 
subjects).
•
Body weight assessment (height is not required).
•
Subject diary return/review.
•
Reminder to complete subject diary on a daily basis.
•
AE reporting.
•
Review withdrawal criteria.
If the Unscheduled Visit is due to an AE, then the C-SSRS is required.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 181 of 203
In addition to the required assessments listed above, the investigator can perform further 
assessments based on his/her clinical judgment and the medical needs of the subject (eg, 
assessments of ECG, laboratory tests, physical examination, neurological examination, 
etc).
Change #42
Section 9.1 Seizure frequency
At the Screening Visit (Visit 1), seizure history will be based on the subject or caregiver 
(including parent/legal guardian) being asked how many seizures the subject has had over the 
past 4 weeks.
During the study, subjects will keep a diary to record daily seizure activity from the 
Screening Visit until the end of the study. The subject should be reminded to bring the diary 
with them to each clinic visit. The following seizure information will be recorded in the 
diary:
•
Seizure type
•
Seizure frequency
Has been changed to:
At the Screening Visit (Visit 1), seizure history will be based on the subject or caregiver 
(including parent/legal representative) being asked how many seizures the subject has had 
over the past 4 weeks.
During the study, subjects will keep a diary to record daily seizure activity from the 
Screening Visit until the end of the study. At each visit and telephone contact the subject 
and/or legal representative should be reminded to complete the subject diary on a daily 
basis and to bring the diary with them to each clinic visit (including Unscheduled Visits). 
The following seizure information will be recorded in the diary:
•
Seizure type
•
Seizure frequency
The investigator should discuss the possibility of the emergence of other seizure types 
with parents and caregivers, and advise that all seizures should be recorded in the 
diary.
Change #43
Section 9.3 Pediatric Quality of Life Inventory
The multidimensional PedsQL scale encompasses the essential core domains for pediatric 
HRQoL measurement: 1) Physical Functioning/Symptoms, 2) Emotional Functioning, 3) 
Social Functioning, and 4) Cognitive/School Functioning. The PedsQL assessment is 
retrospective to the prior month, and individual items are scored using a 5-point Likert scale 
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26 Feb 2015
Clinical Study Protocol
Lacosamide
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Confidential
Page 182 of 203
(never, almost never, sometimes, often, or always). A total health summary score is 
calculated from the sum of the raw scores of the individual items, with higher scores 
indicating higher HRQoL.
Has been changed to:
The multidimensional PedsQL generic core scales encompas the essential core domains for 
pediatric HRQoL measurement: Physical Functioning, Emotional Functioning, Social 
Functioning, and School Functioning. The PedsQL assessment is retrospective to the prior 
4 weeks, and individual items are scored using a 5 point Likert scale (never, almost never, 
sometimes, often, or always). A total health summary score ranging between 0 and 100 is 
calculated from the sum of the raw scores of the individual items, with higher scores 
indicating higher HRQoL.
Change #44
Section 10 ASSESSMENT OF PK
Blood samples for the determination of LCM and concomitant AED plasma concentrations 
will be collected at Visits 2, 6, and 9 (at any time after dosing with the exception of the 
sample at Visit 2, which should be predose) along with clinical chemistry and hematology 
samples (according to the tabular schedule of study procedures in Section 5.2). In each case, 
the time the subject took the most recent dose of LCM and concomitant AEDs and the time 
of blood sampling must be recorded. Actual sampling times will be recorded in the eCRF to 
the minute.
Each blood sample drawn for LCM and concomitant AED plasma concentration 
determination will be split into 2 duplicate samples. The samples will be centrifuged and 
stored at -20°C until shipped to a central laboratory. The central laboratory will store the 
plasma samples at -70°C until analysis. Details of plasma sample collection and processing, 
sample labeling, and shipment will be provided in the laboratory manual.
Has been changed to:
Section 10 ASSESSMENT OF PHARMACOKINETIC/PHARMACODYNAMIC 
VARIABLES
Blood samples for the determination of LCM and concomitant AED plasma concentrations 
will be collected at Visits 2 and 9 (at any time after dosing with the exception of the sample 
at Visit 2, which should be predose) along with clinical chemistry and hematology samples 
(according to the tabular schedule of study procedures in Section 5.2). In each case, the time 
the subject took the most recent dose of LCM and concomitant AEDs and the time of blood 
sampling must be recorded. Actual sampling times will be recorded in the eCRF to the 
minute.
Details of plasma sample collection and processing, sample labeling, and shipment will be 
provided in the laboratory manual.
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 183 of 203
Change #45
Section 11.1.6 Pregnancy
The subject should be withdrawn from the study as soon as pregnancy is known, and the 
following should be completed:
•
The subject should return for the Early Termination Visit.
•
The subject should immediately stop the intake of the IMP or be down-titrated as 
instructed at the Early Termination Visit. 
•
A Safety Follow-Up Visit should be scheduled 2 weeks after the subject has discontinued 
her IMP.
Has been changed to:
The subject should be withdrawn from the study as soon as pregnancy is known, and the 
following should be completed:
•
The subject should return for the Early Termination Visit.
•
The subject should immediately stop the intake of the IMP or be down-titrated as 
instructed at the Early Termination Visit. 
•
A Safety Follow-Up Visit should occur 2 weeks ±2 days after the subject has 
discontinued IMP.
•
A Safety Follow-Up Telephone Contact should occur 30 days (-1/+3 days) after the 
subject has discontinued IMP.
Change #46
Section 11.7.3 12-lead ECG
Care should be taken to assure proper lead placement and quality ECG recordings. Subjects 
should rest in a supine position at least 5 minutes prior to each recording and should be 
motionless during the recording.
Has been changed to:
Care should be taken to assure proper lead placement and quality ECG recordings. Subjects 
should rest in the supine position for approximately 5 minutes before the ECG recordings 
and during the recordings, if possible.
Change #47
Section 11.7.5 Physical examination
The physical examination should be performed by a medically qualified clinician licensed to 
perform the examination, according to the tabular schedule of study procedures in 
Section 5.2. If possible, the same clinician should conduct all physical examinations for the 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 184 of 203
same subject during the study. Clinically significant physical examination findings that have 
emerged or worsened since baseline are to be reported as AEs.
Has been changed to:
The physical examination should be performed by a medically qualified clinician licensed to 
perform the examination, according to the tabular schedule of study procedures in 
Section 5.2. If possible, the same clinician should conduct all physical examinations for the 
same subject during the study. Subsequent to Visit 1, clinically significant physical 
examination findings should be reported as AEs.
Change #48
Section 11.7.5.1 Complete physical examination
The complete physical examination will include cardiac and respiratory function via 
auscultation, temperature, and review of all body systems.
Has been changed to:
The complete physical examination will include cardiac and respiratory function via 
auscultation, temperature, and review of all body systems. Genitourinary and breast 
examinations will not be performed.
Change #49
Section 11.7.11 Assessment of suicidality
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia 
University Medical Center, 2008). For subjects ≥6 years of age, this scale will be used for 
screening as well as to assess suicidal ideation and behavior that may occur during the study. 
The C-SSRS will be completed according to the tabular schedule of study procedures in 
Section 5.2.
The “Since Last Visit” version of the C-SSRS will be used, with the following exceptions:
•
The “Baseline/Screening” version of the C-SSRS should be completed at Visit 1.
•
If a subject turns 6 years of age during the study, the “Already Enrolled” version of the
C-SSRS should be completed at the first visit after the sixth birthday.
Has been changed to:
Suicidality will be assessed by trained study personnel using the C-SSRS (Columbia 
University Medical Center, 2008). For subjects ≥6 years of age, this scale will be used for 
screening as well as to assess suicidal ideation and behavior that may occur during the study. 
The C-SSRS will be completed according to the tabular schedule of study procedures in 
Section 5.2.
The “Since Last Visit” version of the C-SSRS will be used, with the following exceptions:
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 185 of 203
•
The “Baseline/Screening” version of the C-SSRS should be completed at Visit 1.
•
If a subject turns 6 years of age during the study, the “Already Enrolled” version of the
C-SSRS should be completed at the first visit after the sixth birthday.
The C-SSRS is not validated for subjects <6 years of age and will not be used for this 
population. Subjects should be monitored for any changes in mood, ideas, or behavior 
for warning signs of depression. The investigator should be aware of common warning 
signs that might be a signal for risk of depression. For common signs and symptoms of 
depression in children younger than 6 years old, reference should be made to the 
current version of the Diagnostic and Statistical Manual of Mental Disorders. Parents 
and caregivers should also be advised accordingly and effort should be made at clinic 
visits to specifically assess potential depression.
Change #50
Section 13.1 Definition of analysis sets
The analysis set for the preliminary efficacy variables will be the Full Analysis Set and will 
include all subjects in the SS having at least 1 post-Baseline efficacy related assessment.
Has been changed to:
The analysis set for the preliminary efficacy variables will be the Full Analysis Set and will 
include all subjects in the SS having had a Baseline and at least 1 post-Baseline efficacy 
related assessment.
Change #51
Section 13.3.1 Analysis of the primary safety variables
The actual change in the count of generalized spike-wave discharges on 24-hour ambulatory 
EEG from Visit 2 (Baseline Period) to Visit 6 (start of Maintenance Period) will be calculated 
and summarized descriptively.
Has been changed to:
The actual change in the count of generalized spike-wave discharges on 24-hour ambulatory 
EEG from Visit 2 to Visit 6 will be calculated and summarized descriptively.
Change #52
Section 13.3.2 Secondary safety variables
The actual change in the count of 3Hz spike-wave discharges on 24-hour ambulatory EEG 
from Visit 2 (Baseline Period) to Visit 6 (start of Maintenance Period) will be calculated and 
summarized descriptively.
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26 Feb 2015
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Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®). Summary tables for number and percentage of subjects reporting at least 
1 TEAE tabulated by System Organ Class and preferred term will be presented. Furthermore, 
TEAEs that lead to early discontinuation from the study and serious TEAEs will be tabulated. 
Treatment-emergent AEs will be defined as those events which start on or after the date of 
first LCM administration, or whose severity worsens on or after the date of first LCM 
administration. Adverse events occurring within 30 days after last dose of LCM will also be 
considered treatment emergent. 
Has been changed to:
The actual change in the count of 3Hz spike-wave discharges on 24-hour ambulatory EEG 
from Visit 2 to Visit 6 will be calculated and summarized descriptively.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA®). Summary tables for number and percentage of subjects reporting at least 
1 TEAE tabulated by System Organ Class and preferred term will be presented. Furthermore, 
TEAEs that lead to early discontinuation from the study and serious TEAEs will be tabulated. 
Treatment-emergent AEs will be defined as those events which start on or after the date 
of first LCM administration and within 30 days following the date of last LCM 
administration, or whose severity worsens within this time frame.
Change #53
Section 13.4.1 Preliminary efficacy analyses
The actual change in the count of generalized and 3Hz spike-wave discharges on 24-hour 
ambulatory EEG from Visit 2 (Baseline Period) to Visit 9 (end of Maintenance Period) or 
Early Termination will be calculated and summarized descriptively.
Has been changed to:
The actual change in the count of generalized and 3Hz spike-wave discharges on 24-hour 
ambulatory EEG from Visit 2 to Visit 9 or Early Termination will be calculated and 
summarized descriptively.
Change #54
Section 13.4.2 Pharmacokinetic analyses
A listing of LCM and AED plasma concentrations will be presented.
Has been changed to:
A listing of LCM and AED plasma concentrations will be presented. A statistical analysis of 
the effect of LCM on AED concentrations will be performed.
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Lacosamide
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Change #55
Section 13.5 Handling of protocol deviations
After all eCRFs have been retrieved and entered, all queries issued and answered to the extent 
possible, and prior to locking the clinical database, a Data Review Meeting will be held. 
Important protocol deviations (ie, those considered to have an impact on eg, primary safety or 
study conduct) will be identified and reviewed by a panel consisting of the Clinical Project 
Manager, the study biostatistician, study physician, a representative of the monitoring team, 
and other appropriate team members. Important protocol deviations will be listed.
Has been changed to:
Important protocol deviations are deviations from the protocol which potentially could 
have a meaningful impact on either primary efficacy outcome or key safety outcomes 
for an individual subject. The criteria for identifying important protocol deviations and 
the classification of important protocol deviations will be defined within the project 
Data Cleaning Plan. To the extent feasible, rules for identifying protocol deviations will 
be defined without review of the data and without consideration of the frequency of 
occurrence of such deviations. Whenever possible, criteria for identifying important 
protocol deviations will be implemented algorithmically to ensure consistency in the 
classification of important protocol deviations across all subjects.
Important protocol deviations will be reviewed as part of the blinded data cleaning 
meetings prior to database lock to confirm exclusion from analysis sets.
Change #56
Section 13.7 Planned interim analysis and data monitoring
No formal interim analysis is planned for this study; however, data will be presented to and 
reviewed by a DMC. The DMC will oversee the safety of the study by convening to review 
safety data after 15 subjects have completed Visit 6 or withdrawn from the study, then again 
after 30 subjects have completed Visit 6 or withdrawn from the study. The DMC will consist 
of UCB neurologists, a drug safety physician, a biostatistician, and an independent medical 
expert. Study enrollment will not be halted during planned DMC review of the safety data. 
The 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.
Has been changed to:
No formal interim analysis is planned for this study; however, data will be presented to and 
reviewed by a DMC. The DMC will oversee the safety of the study by convening to review 
safety data after 15 subjects have completed Visit 6 or withdrawn from the study, then again 
after 30 subjects have completed Visit 6 or withdrawn from the study. The DMC will consist 
of a UCB neurologist, a neurologist from the European region, a drug safety physician, 
a biostatistician, and an independent medical expert. Study enrollment will not be halted 
during planned DMC review of the safety data. The Sponsor can convene an ad hoc DMC 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 188 of 203
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.
Change #57
Section 13.8 Determination of sample size
A total of 50 evaluable subjects are planned for enrollment for this study across 2 age 
cohorts. The first cohort will consist of approximately 40 subjects between 4 years and <18 
years of age. The second cohort will consist of at least 10 subjects between 1 month and 
<4 years of age. Since the primary objective of this open-label exploratory study is to assess 
the safety and preliminary efficacy of LCM in subjects with generalized seizures and other 
epilepsy syndromes, a sample size of 50 evaluable subjects is deemed adequate for meeting 
the objectives of the study. No formal sample size calculations were performed.
Has been changed to:
A total of 50 evaluable subjects are planned for enrollment for this study across 2 age 
groups. The first age group will consist of approximately 40 subjects between 4 years and 
<18 years of age. The second age group will consist of at least 10 subjects between 1 month 
and <4 years of age. Since the primary objective of this open-label exploratory study is to 
assess the safety and preliminary efficacy of LCM in subjects with generalized seizures and 
other epilepsy syndromes, a sample size of 50 evaluable subjects is deemed adequate for 
meeting the objectives of the study. No formal sample size calculations were performed.
Change #58
Section 16 REFERENCES
The following citations have been added:
Institute of Medicine. Epilepsy across the spectrum: promoting health and 
understanding. Washington, DC: The National Academies Press; 2012. 
Rheims S, Ryvlin P. Profile of perampanel and its potential in the treatment of partial 
onset seizures. Neuropsychiatr Dis Treat. 2013;9:629-37.
17.5
Protocol Amendment 4
Rationale for the amendment
The present amendment has been issued to open enrollment of subjects ≥1 month to <2 years 
of age in SP0966. A weight-based dosing scheme has been established for pediatric subjects 
down to ≥1 month of age, which is consistent with the current SP0966 dosing scheme. This 
dosing scheme is based on safety and PK modeling using data from previous pediatric and 
adults studies.  
In addition, the exclusion of subjects with primary generalized tonic-clonic seizures (PGTCS) 
with a diagnosis of idiopathic generalized epilepsy (IGE) from the SP0966 study population
is removed in this amendment. In the original SP0966 protocol dated 30 May 2012, these 
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 189 of 203
subjects were planned to be included in the exploratory evaluation of LCM treatment in 
pediatric epilepsy syndromes with generalized seizures. However, after finalization of the 
SP0966 protocol, UCB decided that pediatric subjects ≥4 years of age with PGTCS and a 
diagnosis of IGE would instead be evaluated along with adults in a confirmatory 
double-blind, placebo-controlled Phase 3 study. Thus, SP0966 Protocol Amendment 1 
(19 Oct 2012) excluded pediatric subjects in this patient population from SP0966. Due to 
postponement of initiation of the above-mentioned planned confirmatory study in subjects 
≥4 years of age, UCB considers it appropriate to start investigating pediatric subjects with 
PGTCS with a diagnosis of IGE in the SP0966 exploratory study as originally planned. 
Following additional feedback from regulatory agencies, Withdrawal Criterion #6 and 
Exclusion Criterion #16 have been modified. 
It is also clarified that head circumference is to be measured only in subjects <4 years of age.
Modifications and changes
Global changes
The following key changes were made throughout the protocol:
•
Subjects with PGTCS with a diagnosis of IGE are not excluded from the study 
population.
•
Subjects ≥1 month to <2 years of age can now be enrolled into SP0966.
•
Subjects with second- or third-degree heart block are excluded from SP0966, without the 
requirement of being at rest.
•
The AV block withdrawal criterion was modified to second or third degree AV block, 
without the requirement of being awake.
•
Head circumference is to be measured only in subjects <4 years of age.
•
Administrative changes: the name and details of the Clinical Project Manager and the 
SAE Reporting Email address were updated.
Specific changes
Change #1
SPONSOR DECLARATION
Clinical Project Manager
, MD 
Has been changed to:
Clinical Project Manager
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26 Feb 2015
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Lacosamide
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Change #2
STUDY CONTACT INFORMATION
Clinical Project Manager 
Name:
, MD
Address:
UCB BIOSCIENCES GmbH
Alfred-Nobel-Straße 10
40789 Monheim
GERMANY
Phone:
Fax:
Has been changed to:
Clinical Project Manager 
Name:
Address:
UCB BIOSCIENCES Inc.
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
Phone:
Fax:
Change #3
SERIOUS ADVERSE EVENT REPORTING
Email
Global (except Japan): DS_ICT@ucb.com
Has been changed to:
Email
Global (except Japan): DSICT@ucb.com
Change #4
Section 1 SUMMARY, paragraph 2
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26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 191 of 203
The primary variables in this study are changes in the count of generalized spike-wave 
discharges and change in days with any generalized seizures (absence, myoclonic, clonic, 
tonic, tonic-clonic, atonic, and partial evolving to secondarily generalized) from the Baseline 
Period to the Maintenance Period. The above variables reference partial seizures evolving to 
secondarily generalized seizures. While these partial seizures will be summarized as a part of 
the analysis, subjects must have a diagnosis of uncontrolled epilepsy with generalized 
seizures (Type II) according to the International Classification of Epileptic Seizures (1981) 
(see Section 17.1) to possibly be eligible for study participation. In addition to the Type II 
seizures, subjects with a current diagnosis of mixed seizure disorder(s), including both Type I 
and Type II seizures, are also eligible. Subjects with exclusively absence (Type IIA1) or 
atypical absence (Type IIA2) seizures are not eligible. Subjects with primary generalized 
tonic-clonic seizures with a diagnosis of idiopathic generalized epilepsy are also not eligible 
for this study as there is a confirmatory (Phase 3) study evaluating this seizure type. Other 
variables to be assessed include measures of efficacy, plasma concentrations, and other 
measures of safety.
Has been changed to:
The primary variables in this study are changes in the count of generalized spike-wave 
discharges and change in days with any generalized seizures (absence, myoclonic, clonic, 
tonic, tonic-clonic, atonic, and partial evolving to secondarily generalized) from the Baseline 
Period to the Maintenance Period. The above variables reference partial seizures evolving to 
secondarily generalized seizures. While these partial seizures will be summarized as a part of 
the analysis, subjects must have a diagnosis of uncontrolled epilepsy with generalized 
seizures (Type II) according to the International Classification of Epileptic Seizures (1981) 
(see Section 17.1) to possibly be eligible for study participation. In addition to the Type II 
seizures, subjects with a current diagnosis of mixed seizure disorder(s), including both Type I 
and Type II seizures, are also eligible. Subjects with exclusively absence (Type IIA1) or 
atypical absence (Type IIA2) seizures are not eligible. Other variables to be assessed include 
measures of efficacy, plasma concentrations, and other measures of safety.
Change #5
Section 2 INTRODUCTION, last paragraph
SP0966 is a Phase 2, multicenter, open-label exploratory study designed to assess the safety 
and preliminary efficacy of oral LCM as adjunctive therapy for epilepsy syndromes 
associated with generalized (Type II) seizures in pediatric subjects ≥1 month to <18 years of 
age. Initially, only subjects ≥2 years of age will be included in this study. Once the LCM dose 
range has been defined for subjects <2 years of age based on SP847, enrollment of subjects in 
this age group will begin in SP0966.
Has been changed to:
SP0966 is a Phase 2, multicenter, open-label exploratory study designed to assess the safety 
and preliminary efficacy of oral LCM as adjunctive therapy for epilepsy syndromes 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 192 of 203
associated with generalized (Type II) seizures in pediatric subjects ≥1 month to <18 years of 
age. 
Change #6
Section 5.1 Study description, paragraphs 1 and 2
SP0966 is a Phase 2, multicenter, open-label exploratory study designed to assess the safety 
and preliminary efficacy of oral LCM as adjunctive therapy for epilepsy syndromes 
associated with generalized seizures in pediatric subjects ≥1 month to <18 years of age. 
Initially, only subjects ≥2 years of age will be included in this study. Once the LCM dose 
range has been defined for subjects <2 years of age based on confirmation of supportive PK, 
safety, and tolerability dosing data from SP847, enrollment of subjects in this age group will 
begin in SP0966.
Subjects should have a current diagnosis of epilepsy with generalized seizures (Type II) 
according to the International Classification of Epileptic Seizures (1981), see Section 17.1. 
The diagnosis should have been established by clinical history and an EEG with generalized 
spike-wave discharges. In addition to the Type II seizures, subjects with a current diagnosis 
of mixed seizure disorder(s), including both Type I and Type II seizures, are also eligible. 
Subjects with exclusively absence (Type IIA1) or atypical absence (Type IIA2) seizures are 
not eligible. Subjects with primary generalized tonic-clonic seizures with a diagnosis of
idiopathic generalized epilepsy are also not eligible for this study as there is a confirmatory 
(Phase 3) study evaluating this seizure type. 
Has been changed to:
SP0966 is a Phase 2, multicenter, open-label exploratory study designed to assess the safety 
and preliminary efficacy of oral LCM as adjunctive therapy for epilepsy syndromes 
associated with generalized seizures in pediatric subjects ≥1 month to <18 years of age. 
Subjects should have a current diagnosis of epilepsy with generalized seizures (Type II) 
according to the International Classification of Epileptic Seizures (1981), see Section 17.1. 
The diagnosis should have been established by clinical history and an EEG with generalized 
spike-wave discharges. In addition to the Type II seizures, subjects with a current diagnosis 
of mixed seizure disorder(s), including both Type I and Type II seizures, are also eligible. 
Subjects with exclusively absence (Type IIA1) or atypical absence (Type IIA2) seizures are 
not eligible. 
Change #7
Section 5.2 Schedule of study assessments, Table 5-1
Assessments
Head circumference 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 193 of 203
Has been changed to:
Assessments
Head circumference 
(subjects <4 years)
Change #8
Section 6.1 Inclusion criteria, criterion 3
3. Subject is male or female, ≥1 month to <18 years of age. (Note, until the LCM dose range 
has been defined in subjects <2 years of age based on SP847, only subjects ≥2 years of 
age will be enrolled.) For preterm infants <1 year old, the corrected gestational age should 
be used when determining eligibility. The generally accepted definition of corrected 
gestational age, which is calculated by subtracting the number of weeks born before 
37 weeks of gestation from the chronological age, will be used for this study.
Has been changed to:
3.
Subject is male or female, ≥1 month to <18 years of age. For preterm infants <1 year old, 
the corrected gestational age should be used when determining eligibility. The generally 
accepted definition of corrected gestational age, which is calculated by subtracting the 
number of weeks born before 37 weeks of gestation from the chronological age, will be 
used for this study.
Change #9
Section 6.2 Exclusion criteria, criterion 6
6. Subject has primary generalized tonic-clonic seizures with a diagnosis of idiopathic 
generalized epilepsy.
Has been removed
Change #10
Section 6.2 Exclusion criteria, criterion 17
17. Subject has a clinically relevant ECG abnormality, in the opinion of the principal 
investigator (ie, second or third degree heart block at rest or a corrected QT interval 
[QTc] greater than 450ms).
Has been changed to:
17. Subject has a clinically relevant ECG abnormality, in the opinion of the principal 
investigator (ie, second- or third-degree heart block or a corrected QT interval [QTc] 
greater than 450ms).
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 194 of 203
Change #11
Section 6.3 Withdrawal criteria, criterion 6
6. Subject develops a second degree AV block while awake or develops a third degree AV 
block.
Has been changed to:
6. Subject develops second- or third-degree AV block.
Change #12
Section 8.1.1 Visit 1 (Week -6) Screening Visit
•
Head circumference.
Has been changed to:
•
Head circumference in subjects <4 years of age.
Change #13
Section 8.3.4 Visit 9 (Week 18)/Early Termination Visit
•
Head circumference.
Has been changed to:
•
Head circumference in subjects <4 years of age.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 195 of 203
17.6
Protocol Amendment 5
Rationale for the amendment
The present amendment has been issued to exclude subjects with primary generalized 
tonic-clonic seizures with a diagnosis of idiopathic generalized epilepsy from the SP0966 
study population. A confirmatory study (SP0982) to investigate the effect of LCM in this 
population is being conducted and, therefore, this population will not be included in SP0966.
As per the recommendations made by the USA FDA, the creatinine clearance has been
changed from less than 50mL/min to less than 30mL/min.
In addition, minor administrative changes and edits were made.
Modifications and changes
Global changes
The following key changes were made throughout the protocol:
•
Subjects with primary generalized tonic-clonic seizures with a diagnosis of idiopathic 
generalized epilepsy were excluded from the study population.
•
Exclusion criterion for creatinine clearance rate has changed from <50mL/min to 
<30mL/min.
•
Exclusion criterion number 20 has been reworded to clarify that the excluded sodium 
channelopathies are cardiac.
•
Administrative changes: the name of the Study Physician and the name of the CRO have 
been updated, and the Sponsor Declaration has been updated for electronic signature. 
•
Russia has been removed as a participating country.
Specific changes
Change #1
SPONSOR DECLARATION
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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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 196 of 203
Clinical Project Manager
_____________________________
Date/Signature
Clinical Trial Biostatistician
, MA
_____________________________
Date/Signature
Study Physician
, MD
_____________________________
Date/Signature
Clinical Program Director 
, BS
_____________________________
Date/Signature
Has been revised and moved to Section 19:
19. SPONSOR DECLARATION 
I confirm that I have carefully read and understood this protocol and agree to conduct 
this clinical study as outlined in this protocol, according to current GCP.
Change #2
STUDY CONTACT INFORMATION
Sponsor Study Physician
Name:
, MD
Address:
UCB BIOSCIENCES Inc.
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
Phone:
Fax:
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 197 of 203
Has been changed to:
Sponsor Study Physician
Name:
, MD
Address:
UCB BIOSCIENCES Inc.
8010 Arco Corporate Drive
Raleigh, NC 27617
UNITED STATES
Phone:
Fax:
Change #3
Clinical Monitoring Contract Research Organization
Name:
PRA International
Address:
4130 Park Lake Avenue, Suite 400 
Raleigh, NC 27612 
UNITED STATES
Phone:
+1 919 786 8200
Fax:
+1 919 786 8201
Has been changed to:
Name:
PRA Health Sciences
Address:
4130 Park Lake Avenue, Suite 400 
Raleigh, NC 27612 
UNITED STATES
Phone:
+1 919 786 8200
Fax:
+1 919 786 8201
Change #4
Section 1 SUMMARY, paragraph 3
Approximately 50 subjects will be enrolled in this study across approximately 50 sites in 
Europe, Russia, and North America, and other regions as deemed necessary.
Has been changed to:
Approximately 50 subjects will be enrolled in this study across approximately 50 sites in 
Europe and North America, and other regions as deemed necessary.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 198 of 203
Change #5
Section 5.1 Study description, Paragraph 2
Subjects should have a current diagnosis of epilepsy with generalized seizures (Type II) 
according to the International Classification of Epileptic Seizures (1981), see Section 17.1. 
The diagnosis should have been established by clinical history and an EEG with generalized 
spike-wave discharges. In addition to the Type II seizures, subjects with a current diagnosis 
of mixed seizure disorder(s), including both Type I and Type II seizures, are also eligible. 
Subjects with exclusively absence (Type IIA1) or atypical absence (Type IIA2) seizures are 
not eligible.
Has been changed to:
Subjects should have a current diagnosis of epilepsy with generalized seizures (Type II) 
according to the International Classification of Epileptic Seizures (1981), see Section 17.1. 
The diagnosis should have been established by clinical history and an EEG with generalized 
spike-wave discharges. In addition to the Type II seizures, subjects with a current diagnosis 
of mixed seizure disorder(s), including both Type I and Type II seizures, are also eligible. 
Subjects with exclusively absence (Type IIA1) or atypical absence (Type IIA2) seizures are 
not eligible. Subjects with primary generalized tonic-clonic seizures with a diagnosis of 
idiopathic generalized epilepsy are not eligible for this study as there is a confirmatory 
(Phase 3) study evaluating this seizure type.
Change #6
Section 5.1.3 Anticipated regions and countries 
This study will be conducted at approximately 50 sites in Europe, Russia, and North 
America, and other regions as deemed necessary.
Has been changed to:
This study will be conducted at approximately 50 sites in Europe and North America, and 
other regions as deemed necessary.
Change #7
Section 6.1 Inclusion criteria and Section 6.2 Exclusion criteria
Inclusion criterion 2
2. Subject and caregiver (which may be a parent, a legal representative, or other caregiver) 
are willing and able to comply with all study requirements including maintaining a daily 
seizure diary.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 199 of 203
Has been changed to:
2. Subject and/or caregiver (which may be a parent, a legal representative, or other 
caregiver) are willing and able to comply with all study requirements including maintaining a 
daily seizure diary.
Exclusion criterion 6
The following exclusion criterion has been added:
6. Subject has primary generalized tonic-clonic seizures with a diagnosis of idiopathic 
generalized epilepsy.
Exclusion criterion 15
15. Subject has impaired renal function (ie, creatinine clearance is lower than 50mL/min) at 
Visit 1.
Has been changed to:
15. Subject has impaired renal function (ie, creatinine clearance is lower than 30mL/min) at 
Visit 1.
Exclusion criterion 20
20. Subject has a known sodium channelopathy, such as Brugada syndrome.
Has been changed to:
20. Subject has a known cardiac sodium channelopathy, such as Brugada syndrome.
Change #8
Section 7.2 Treatment(s) to be administered
Table 7-1:
Lacosamide dose titration during the Titration Period
Body weight 
category 
(formulation)
Flexible doses for the Titration Period by study week
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
<50kg (oral 
solution)
2mg/kg/day
4mg/kg/day
6mg/kg/day
8mg/kg/day
10mg/kg/
day
12mg/kg/
day
≥50kg 
(tablets/oral 
solution)
100mg/day
200mg/day
300mg/day
400mg/day
500mg/day
600mg/day
Note: Subjects weighing ≥50kg who are unable or unwilling to swallow tablets can be dispensed LCM oral 
solution instead.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 200 of 203
Has been changed to:
Table 7-1:
Lacosamide dose titration during the Titration Period
Body weight 
category 
(formulation)
Flexible doses for the Titration Period by study week
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6
<50kg (oral 
solution)
2mg/kg/day
4mg/kg/day
6mg/kg/day
8mg/kg/day
10mg/kg/
day
12mg/kg/
day
≥50kg 
(tablets/oral 
solution)
100mg/day
200mg/day
300mg/day
400mg/day
500mg/day
600mg/day
LCM=lacosamide
Note: Subjects weighing ≥50kg who are unable or unwilling to swallow tablets can be dispensed LCM oral 
solution instead.
Change #9
Section 11.1.4 Follow up of AEs
If an AE is still ongoing at the end of the study for a subject, follow up should be provided 
until resolution/stable level of sequelae is achieved, or until the investigator no longer deems 
that it is clinically significant, or until the subject is lost to follow up. If no follow up is 
provided, the investigator must provide a justification. The follow up will usually be 
continued for 30 days after the subject has discontinued his/her IMP.
Has been changed to:
If an AE is ongoing at the end of the study for a subject, follow up should be provided until 
resolution/stable level of sequelae is achieved, or until the investigator no longer deems that it 
is clinically significant, or until the subject is lost to follow up. If no follow up is provided, 
the investigator must provide a justification. The follow up will usually be continued for
30 days after the subject has discontinued his/her IMP.
Change #10
Section 11.4 Immediate reporting of AEs
The following AEs must be reported immediately:
Has been changed to:
The following AEs must be reported immediately by the investigator to the sponsor:
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 201 of 203
Change #11
Section 12.1 Adherence to protocol
The investigator should not deviate from the protocol. In medical emergencies, the 
investigator may use his/her medical judgment and may remove a study participant from 
immediate hazard before notifying UCB (or its representative) and the IRB/IEC in writing 
regarding the type of emergency and the course of action taken.
Has been changed to:
The investigator should not deviate from the protocol. However, the investigator should take 
any measure necessary in deviation from or not defined by the protocol in order to 
protect clinical study subjects from any immediate hazard to their health and safety. In 
this case, this action should be taken immediately, without prior notification of the 
regulatory authority, IRB/IEC, or sponsor. 
After implementation of such measure, the investigator must notify the Clinical Project 
Manager of the sponsor within 24 hours and follow any local regulatory requirements.
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 202 of 203
18
DECLARATION AND SIGNATURE OF INVESTIGATOR
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current GCP and local laws and 
requirements.
I will ensure that all subinvestigators and other staff members read and understand all aspects 
of this protocol.
I have received and read all study-related information provided to me.
The objectives and content of this protocol as well as the results deriving from it will be 
treated confidentially, and will not be made available to third parties without prior 
authorization by UCB.
All rights of publication of the results reside with UCB, unless other agreements were made 
in a separate contract.
Investigator:
__________________________________
Printed name
__________________________________
Date/Signature
REDACTED COPY 
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UCB
26 Feb 2015
Clinical Study Protocol
Lacosamide
SP0966
Confidential
Page 203 of 203
19
SPONSOR DECLARATION 
I confirm that I have carefully read and understood this protocol and agree to conduct this 
clinical study as outlined in this protocol, according to current GCP.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


ELECTRONIC SIGNATURES
Signed by 
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Server Approval Date 
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SAP_000.pdf: 
UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 1 of 53
STATISTICAL ANALYSIS PLAN 
Study: SP0966
Product: Lacosamide
A MULTI-CENTER, OPEN-LABEL, EXPLORATORY STUDY TO INVESTIGATE THE 
SAFETY AND EFFICACY OF LACOSAMIDE AS ADJUNCTIVE THERAPY IN SUBJECTS 
≥1 MONTH TO <18 YEARS WITH EPILEPSY SYNDROMES ASSOCIATED WITH 
GENERALIZED SEIZURES
SAP/Amendment Number
Date
Final SAP
28 Apr 2015
Amendment 1, Post Dry-run
06 March 2018
Confidentiality Statement
Confidential
This document is the property of UCB and may not – in full or in part – be passed on, reproduced, 
published, or otherwise used without the express permission of UCB.
REDACTED 
r 2015
2015
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 2 of 53
TABLE OF CONTENTS
LIST OF ABBREVIATIONS....................................................................................................5
1
INTRODUCTION .............................................................................................................7
2
PROTOCOL SUMMARY.................................................................................................7
2.1 Study objectives.................................................................................................................7
2.2 Study variables...................................................................................................................7
2.2.1
Safety variables......................................................................................................7
2.2.1.1
Primary safety variables ..............................................................................7
2.2.1.2
Secondary safety variables ..........................................................................7
2.2.1.3
Other variables assessing safety..................................................................8
2.2.1.4
Exploratory Safety variables .......................................................................8
2.2.2
Efficacy variables ..................................................................................................8
2.2.2.1
Preliminary efficacy variables.....................................................................8
2.2.2.2
Exploratory efficacy variables.....................................................................9
2.2.3
Pharmacokinetic and pharmacodynamic variables..............................................10
2.3 Study design and conduct ................................................................................................10
2.4 Determination of sample size...........................................................................................10
3
DATA ANALYSIS CONSIDERATIONS......................................................................11
3.1 General presentation of summaries and analyses ............................................................11
3.2 General study level definitions ........................................................................................11
3.2.1
Last dose of LCM ................................................................................................11
3.2.2
Relative day .........................................................................................................11
3.2.3
Study periods .......................................................................................................12
3.2.4
Last Visit..............................................................................................................12
3.2.5
Age and age groups .............................................................................................12
3.3 Definition of Baseline values...........................................................................................13
3.4 Protocol deviations...........................................................................................................13
3.5 Analysis sets.....................................................................................................................13
3.5.1
Safety Set.............................................................................................................13
3.5.2
Full Analysis Set..................................................................................................14
3.5.3
Pharmacokinetic Per Protocol Set .......................................................................14
3.6 Treatment assignment and treatment groups ...................................................................14
3.7 Center pooling strategy....................................................................................................14
3.8 Coding dictionaries ..........................................................................................................14
3.9 Changes to protocol-defined analyses..............................................................................14
4
STATISTICAL/ANALYTICAL ISSUES.......................................................................14
4.1 Adjustments for covariates...............................................................................................14
4.2 Handling of dropouts or missing data..............................................................................14
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06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 3 of 53
4.2.1
Visit mapping in case of premature discontinuation ...........................................14
4.2.2
Missing data.........................................................................................................14
4.2.3
Incomplete or missing dates for adverse events and concomitant medication....15
4.2.4
Incomplete dates for the last administration of LCM..........................................16
4.3 Interim analyses and data monitoring..............................................................................16
4.4 Multicenter studies...........................................................................................................16
4.5 Multiple comparisons/multiplicity...................................................................................17
4.6 Use of an efficacy subset of subjects ...............................................................................17
4.7 Active-control studies intended to show equivalence......................................................17
4.8 Examination of subgroups ...............................................................................................17
5
STUDY POPULATION CHARACTERISTICS.............................................................17
5.1 Subject disposition...........................................................................................................17
5.2 Protocol deviations...........................................................................................................18
6
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS ........................18
6.1 Demographics ..................................................................................................................18
6.2 Other Baseline characteristics..........................................................................................18
6.3 Medical history and concomitant diseases.......................................................................20
6.4 Prior and concomitant medications..................................................................................20
7
MEASUREMENTS OF TREATMENT COMPLIANCE...............................................21
7.1 Derivation of compliance.................................................................................................21
7.2 Presentation of compliance..............................................................................................21
8
SAFETY ANALYSES.....................................................................................................21
8.1 Primary safety variables...................................................................................................21
8.1.1
Generalized spike-wave discharges.....................................................................21
8.1.2
Generalized seizures ............................................................................................22
8.2 Secondary safety variables...............................................................................................22
8.2.1
3Hz spike-wave discharges..................................................................................22
8.2.2
Adverse events.....................................................................................................22
8.3 Exploratory safety variables.............................................................................................23
8.4 Extent of exposure ...........................................................................................................23
8.5 Clinical laboratory evaluations ........................................................................................24
8.6 Vital signs, physical findings, and other observations related to safety..........................25
8.6.1
Vital signs, body weight, height, BMI, and head circumference ........................25
8.6.2
Electrocardiograms..............................................................................................26
8.6.3
Physical and neurological examination ...............................................................27
8.6.4
Tanner stage assessment......................................................................................28
8.6.5
Achenbach Child Behavior Checklist..................................................................28
8.6.6
BRIEF-P and BRIEF assessment.........................................................................29
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06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 4 of 53
9
ANALYSES OF EFFICACY VARIABLES...................................................................31
9.1 Preliminary Efficacy Variables........................................................................................31
9.1.1
Seizure days.........................................................................................................31
9.1.2
Clinical global impression of change...................................................................31
9.1.3
Caregiver’s global impression of change ............................................................32
9.1.4
Pediatric quality of life inventory........................................................................32
9.1.5
Health care resource use ......................................................................................33
9.2 Exploratory  Efficacy Variables.......................................................................................33
10
PHARMACOKINETICS.................................................................................................34
10.1 Descriptive statistics of LCM and AED plasma concentrations......................................34
10.2 Population pharmacokinetics and exposure response......................................................34
11
OTHER ANALYSES ......................................................................................................34
12
REFERENCES ................................................................................................................35
13
APPENDICES .................................................................................................................36
13.1 Significant Adverse Events..............................................................................................36
13.2 Marked abnormality criteria for laboratory data..............................................................37
13.2.1
Marked abnormality criteria for hematology data...............................................37
13.2.2
Marked abnormality criteria for chemistry data ..................................................38
14
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN (SAP)......................42
14.1 Amendment 1...................................................................................................................42
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE.....................................................53
LIST OF TABLES
Table 8‒1:
Vital Signs Abnormality Criteria.....................................................................25
Table 8‒2:
Electrocardiogram Abnormality Criteria .........................................................26
Table 8‒1:
CBCL/1½-5......................................................................................................28
Table 8‒2:
CBCL/6-18.......................................................................................................29
Table 8‒3:
BRIEF-P questionnaire scoring .......................................................................29
Table 8‒4:
BRIEF questionnaire scoring...........................................................................30
Table 13-1:
List of other significant AEs............................................................................36
Table 13‒2:
Hematology abnormality criteria.....................................................................37
Table 13‒3:
Chemistry abnormality criteria ........................................................................38
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 5 of 53
LIST OF ABBREVIATIONS
AE
adverse event
AED
antiepileptic drug 
Bayley-III
Bayley Scales of Infant and Toddler Development®, 
Third Edition
BMI
body mass index
BP
blood pressure 
BRIEF®
Behavior Rating Inventory of Executive Function®
BRIEF®-P
Behavior Rating Inventory of Executive Function®-
Preschool Version
CBCL
Child Behavior Checklist
CV
coefficient of variation
DEM
Data Evaluation Meeting
DMC
Data Monitoring Committee
ECG
electrocardiogram
eCRF
electronic Case Report form
EEG
electroencephalogram
ER
emergency room
ET
Early Termination
FAS
Full Analysis Set
FSH
follicle stimulating hormone
GEC
Global Executive Composite
ILAE
International League Against Epilepsy
LCM
lacosamide
LH
luteinizing hormone
MedDRA®
Medical Dictionary for Regulatory Activities
PedsQL
Pediatric Quality of Life Inventory
PK
pharmacokinetic
PT
preferred term
PK-PPS
Pharmacokinetic Per Protocol Set
SAP
Statistical Analysis Plan
SD
standard deviation
SOC
system organ class
SPD
Specification of Protocol Deviations
SS
Safety Set
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06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 6 of 53
T3
triiodothyronine
T4
thyroxine
TEAE
treatment-emergent adverse event
TEMA
treatment-emergent markedly abnormal
TSH
thyroid stimulating hormone
WHO-DD
World Health Organization Drug Dictionary
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 7 of 53
1
INTRODUCTION
This Statistical Analysis Plan (SAP) defines the scope of statistical analyses and provides a 
detailed description of statistical methodology for the statistical analyses to support the final 
clinical study report for SP0966.
2
PROTOCOL SUMMARY
Protocol Date:
30 May 2012
Amendment 1:
19 Oct 2012
Amendment 2:
09 Nov 2012
Amendment 3:
21 Jun 2013
Amendment 4:
25 Feb 2014
Amendment 5: 
26 Feb 2015
2.1
Study objectives
The objectives of this study are:
!
To evaluate the safety and tolerability of lacosamide (LCM) when added to 1 to 3 
concomitant antiepileptic drugs (AEDs) in pediatric subjects with epilepsy syndromes 
associated with generalized seizures
!
To obtain preliminary efficacy data of LCM on seizure frequency in pediatric epilepsy 
syndromes associated with generalized seizures
!
An additional objective is to evaluate the pharmacokinetic (PK) of LCM in subjects ≥1 
month to <18 years of age.
2.2
Study variables
2.2.1
Safety variables
2.2.1.1
Primary safety variables
The primary variables assessing safety are:
!
Changes in count of generalized spike-wave discharges on 24-hour ambulatory 
electroencephalogram (EEG) from Visit 2 to Visit 6 
!
Change in days with any generalized seizures (absence, myoclonic, clonic, tonic, tonic 
clonic, atonic, partial evolving to secondarily generalized) per 28 days from the Baseline 
Period to the Maintenance Period 
The assessment of seizure days will be based on the seizure diary.
2.2.1.2
Secondary safety variables
The secondary variables assessing safety are:
!
Changes in count of 3Hz spike-wave discharges (during waking hours) on 24-hour 
ambulatory EEG from Visit 2 to Visit 6 
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 8 of 53
!
Adverse events (AEs) as reported spontaneously by the subject and/or caregiver, or observed 
by the investigator
!
Subject withdrawals due to AEs
2.2.1.3
Other variables assessing safety
The other safety variables are:
!
Changes in hematology, clinical chemistry, and urinalysis parameters
!
Changes in hormone status (follicle stimulating hormone [FSH], luteinizing hormone [LH], 
triiodothyronine [T3], thyroxine [T4], thyroid stimulating hormone [TSH], and testosterone, 
as appropriate)
!
Changes in 12-lead electrocardiograms (ECGs)
!
Changes in vital sign measurements (ie, blood pressure [BP] and pulse rate)
!
Physical and neurological examination findings
!
Changes in body weight, height, and calculated body mass index (BMI)
!
Changes in Tanner Stage (if applicable)
!
Behavioral assessment (Achenbach Child Behavior Checklist [CBCL/1½-5 or CBCL/6-18]) 
for pediatric subjects ≥18 months of age
2.2.1.4
Exploratory Safety variables
!
Decrease in generalized spike-wave discharges on 24-hour ambulatory EEG by syndrome 
subgroups
2.2.2
Efficacy variables
2.2.2.1
Preliminary efficacy variables
Variables used to assess preliminary efficacy will include:
!
Change in days with absence seizures per 28 days from the Baseline Period to the 
Maintenance Period
!
Change in days with myoclonic seizures per 28 days from the Baseline Period to the 
Maintenance Period
!
Change in days with clonic seizures per 28 days from the Baseline Period to the Maintenance 
Period 
!
Change in days with tonic seizures per 28 days from the Baseline Period to the Maintenance 
Period
!
Change in days with tonic-clonic seizures per 28 days from the Baseline Period to the 
Maintenance Period
!
Change in days with atonic seizures per 28 days from the Baseline Period to the Maintenance 
Period
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06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 9 of 53
!
Change in days with partial evolving to secondarily generalized seizures per 28 days from the 
Baseline Period to the Maintenance Period
!
Percent change in days with any generalized seizures (absence, myoclonic, clonic, tonic, 
tonic-clonic, atonic, partial evolving to secondarily generalized) per 28 days from the 
Baseline Period to the Maintenance Period
!
Percent change in days with absence seizures per 28 days from the Baseline Period to the 
Maintenance Period
!
Percent change in days with myoclonic seizures per 28 days from the Baseline Period to the 
Maintenance Period
!
Percent change in days with clonic seizures per 28 days from the Baseline Period to the 
Maintenance Period 
!
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Maintenance Period
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Maintenance Period
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Percent change in days with atonic seizures per 28 days from the Baseline Period to the 
Maintenance Period
!
Percent change in days with partial evolving to secondarily generalized seizures per 28 days 
from the Baseline Period to the Maintenance Period
!
Changes in count of generalized spike-wave discharges on 24-hour ambulatory EEG from 
Visit 2 to Visit 9 or at Early Termination (ET)
!
Changes in count of 3Hz spike-wave discharges (during waking hours) on 24-hour 
ambulatory EEG from Visit 2 to Visit 9 or at ET
!
Clinical Global Impression of Change upon completion of the Maintenance Period 
(Termination) or at ET
!
Caregiver’s Global Impression of Change upon completion of the Maintenance Period 
(Termination) or at ET
!
Change in quality of life assessment (Pediatric Quality of Life Inventory [PedsQL™]) for 
subjects ≥1 month to ≤18 years of age
2.2.2.2
Exploratory efficacy variables
!
At least 50 percent reduction in generalized seizures per 28 days by study period (titration 
and maintenance period) and syndrome subgroup
!
Increase in generalized seizures of more than 25 percent per 28 days during the study period 
by syndrome subgroup
!
Percent change in days with any generalized seizures per 28 days during the study period by 
syndrome subgroup
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06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 10 of 53
2.2.3
Pharmacokinetic and pharmacodynamic variables
Plasma concentrations of LCM and concomitant AEDs will be obtained in order to: 
!
Develop a population PK model of LCM
!
Investigate the effect of LCM on the steady-state plasma concentrations of concomitant 
AEDs
!
Investigate the correlation between LCM plasma concentrations and efficacy or safety
2.3
Study design and conduct
SP0966 is a Phase 2, multicenter, open-label exploratory study designed to assess the safety and 
preliminary efficacy of oral LCM as adjunctive therapy for epilepsy syndromes associated with 
generalized seizures in pediatric subjects ≥1 month to <18 years of age. 
The study treatment is LCM in either the oral solution formulation or tablet formulation. The 
formulation of LCM to be administered is based on the weight of the subject. 
Subjects will not be randomized, but all subjects who sign the informed consent form at Visit 1 
will be assigned a unique identification number. 
Approximately 50 subjects will be enrolled at approximately 50 sites in Europe, and North 
America, and other regions as deemed necessary. It is planned to enroll approximately 
40 subjects between 4 years and <18 years of age and at least 10 subjects between 1 month and 
<4 years of age.
The study will begin with subject screening at Visit 1 and will consist of a 6-week prospective 
Baseline Period. If all inclusion criteria are met and no exclusion criterion is met, the subject will 
begin a 6-week Titration Period (LCM dosing flexibility allowed based on tolerability) starting at 
Visit 2. Subjects will initiate treatment with LCM oral solution at 2mg/kg/day, or LCM tablets at 
100mg/day based on body weight. The dose will be titrated to a level to optimize tolerability and 
seizure control, not to exceed 12mg/kg/day (oral solution) for subjects weighing <50kg, or 
600mg/day (tablets/oral solution) in subjects weighing ≥50kg. Subjects will increase the LCM 
dose in a stepwise fashion on a weekly basis to optimize tolerability and seizure control.
At the end of the Titration Period (Visit 6), a 12-week Maintenance Period will begin. The LCM 
dose will remain stable throughout the Maintenance Period. Subjects who require a change in 
dose during the Maintenance Period will be withdrawn from the study. 
The end of the Maintenance Period will be Visit 9, or, if subjects withdraw early, the ET Visit. 
Subjects may be eligible for participation in the additional open-label study (SP848). Subjects 
who choose not to participate in the open-label study or subjects who discontinue due to other 
reasons will enter a 2- to 4-week Taper Period followed by a Safety Follow-Up Visit 2 weeks 
(±2 days) after the final dose of LCM and a Safety Follow-Up Telephone Contact 30 days 
(-1/+3 days) after the final dose of LCM. 
A Data Monitoring Committee (DMC) will oversee the safety of the study.
2.4
Determination of sample size
A total of 50 evaluable subjects are planned for enrollment for this study across 2 age groups. 
The first age group will consist of approximately 40 subjects between 4 years and <18 years of 
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 11 of 53
age. The second age group will consist of at least 10 subjects between 1 month and <4 years of 
age. Since the primary objective of this open-label exploratory study is to assess the safety and 
preliminary efficacy of LCM in subjects with generalized seizures and other epilepsy syndromes, 
a sample size of 50 evaluable subjects is deemed adequate for meeting the objectives of the 
study. No formal sample size calculations were performed.
3
DATA ANALYSIS CONSIDERATIONS
3.1
General presentation of summaries and analyses
Statistical analysis and generation of tables, figures, subject data listings, and statistical output 
will be performed using SAS Version 9.4 or higher. All tables and listings will use Courier New 
font size 9. 
Descriptive statistics will be displayed to provide an overview of the study results. If not stated 
otherwise, all summaries will be displayed overall and by age group (≥ 1 month to <4 years, ≥4 
to <12 years, and ≥12 to <18 years). For categorical parameters, the number and percentage of 
subjects in each category will be presented. If not stated otherwise, the denominator for 
percentages will be based on the number of subjects in the respective population. Unless 
otherwise noted, all percentages will be displayed to 1 decimal place. No percentage will be 
displayed for zero counts, and no decimal will be presented when the percentage is 100%. For 
continuous parameters, descriptive statistics will include number of subjects (n), mean, standard 
deviation (SD), median, minimum, and maximum.
Decimal places for descriptive statistics will always apply the following rules:
!
“n” will be an integer.
!
Mean, SD, and median will use 1 additional decimal place compared to the original data.
!
Coefficient of variance (CV[%]) will be presented with 1 decimal place.
!
Minimum and maximum will have the same number of decimal places as the original value.
A complete set of data listings containing all documented data and all calculated data (eg, change 
from Baseline) will be generated, and will be sorted by site, subject number and visit (where 
applicable).
3.2
General study level definitions
3.2.1
Last dose of LCM
Unless otherwise noted, all references to the last dose of LCM in this SAP refer to the last dose 
of LCM within the study (eg, including the Taper Period). The last dose of LCM during the 
Treatment Period will be defined as the last dose during the Titration and Maintenance Periods.
3.2.2
Relative day
The relative day of a visit or an event with respect to the first intake of LCM will be presented in 
subject data listings. Relative day will be calculated as follows:
!
If the visit/event date occurred prior to the first intake of LCM, the relative day is calculated 
as visit/event date minus first LCM dose date. In subject data listings, relative days based on 
this situation will be preceded by a ‘-‘.
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 12 of 53
!
If the visit/event date occurred on or after the first intake of LCM but prior to the last dose of 
LCM, the relative day is calculated as visit/event date minus first LCM dose date + 1.
!
If the visit/event date occurred after the date of last dose of LCM, the relative day is 
calculated as visit/event date minus last dose date. In subject data listings, relative days based 
on this situation will be preceded by a ‘+’.
Relative days will not be presented for partial or missing dates.
3.2.3
Study periods
For the purpose of analyses, the following periods are defined.
!
Baseline Period: 
The Baseline Period is defined as the period of time from the date of Visit 1 to 1 day prior to 
the date of first dose of LCM. For the definition of Baseline values see Section 3.3.
!
Titration Period: 
The Titration Period is defined as the period of time from the date of first dose of LCM to the 
date of Visit 6 or the date of ET, whatever occurs first. If Visit 6 and ET are missing the 
Titration Period ends at the date of last dose of LCM.
!
Maintenance Period: 
The Maintenance Period is defined as the period of time from the day after the date of Visit 6 
to the date of Visit 9/ET. If Visit 9/ET is missing the Maintenance Period ends at the date of 
last dose of LCM.
!
Treatment Period:
The Treatment Period is defined as the combined Titration and Maintenance Period, ie, starts 
at the date of first dose of LCM and ends at Visit 9/ET. If Visit 9/ET is missing the 
Maintenance Period ends at the date of last dose of LCM.
3.2.4
Last Visit
The Last Visit for all assessments in SP0966 is the last non-missing assessment during the 
Treatment Period. This cannot be the same assessment as the baseline assessment. All scheduled 
and unscheduled assessments within this time period will be considered. Last Visit will be 
determined separately for each study procedure where Last Visit is mentioned within this 
document.
3.2.5
Age and age groups
The age (at enrollment) will be given in years (with 2 decimals) and will be derived with the 
following formula:
Age (years) = (date of informed consent - date of birth) / 365.25
Partial dates will not be completed. If it is not possible to calculate the age due to incomplete or 
missing date information the age as documented at Visit 1 will be used:
Age (years) = years part of age in CRF + (month part of age in CRF / 12)
If not stated otherwise, the following age groups will be used for the presentation of results: 
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 13 of 53
!
≥ 1 month to <4 years, 
!
≥4 to <12 years, and 
!
≥12 to <18 years.
For the derivation of (markedly) abnormal values (see Sections 8.5, 8.6.1, and 8.6.2) the age at 
assessment will be used. This will be derived as follows:
!
For subject with a complete date of birth, use the date of birth to calculate the age at the time 
of measurement.
!
For subject with a partial date of birth with available information about year and month, use 
the first day of the month to impute the date of birth and use the imputed date of birth to 
calculate age at the time of measurement.
!
For subject with a partial date of birth with available information about year only, use age as 
given in the eCRF and add the time between measurement and informed consent (ie, [date of 
measurement – date of informed consent] / 365.25).
3.3
Definition of Baseline values
Unless otherwise specified, Baseline will be based on the last nonmissing data collected prior to 
the first dose of LCM, ie, assessments on Visit 1 or Visit 2. It is possible that values measured on 
the day of first dose of LCM (Visit 2 [start of Titration Period]) are assigned to the Baseline 
Period for summary purposes.
3.4
Protocol deviations
Important protocol deviations are deviations from the protocol which could potentially have a 
meaningful impact on the primary or secondary safety outcomes or preliminary efficacy 
outcomes for an individual subject. The criteria for identifying important protocol deviations and 
the classification of important protocol deviations will be defined separately in the Specification
of Protocol Deviations (SPD) document. To the extent feasible, rules for identifying protocol 
deviations will be defined without review of the data and without consideration of the frequency 
of occurrence of such deviations. Whenever possible, criteria for identifying important protocol 
deviations will be implemented algorithmically to ensure consistency in the classification of 
important protocol deviations across all subjects.
Important protocol deviations will be reviewed as part of the Data Evaluation Meeting (DEM) 
prior to database lock.
3.5
Analysis sets
The analysis set for subject disposition will be based on All Subjects Screened. Safety variables 
will be summarized for the Safety Set (SS); efficacy variables will be summarized for the Full 
Analysis Set (FAS). Select PK analysis may be based on the Pharmacokinetic Per-Protocol Set 
(PK-PPS). All other parameters will be summarized using the SS.
3.5.1
Safety Set
The primary analysis set will be the SS and will include all enrolled subjects who take at least 
1 dose of LCM.
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 14 of 53
3.5.2
Full Analysis Set
The analysis set for the preliminary efficacy variables will be the FAS and will include all 
subjects in the SS having had a Baseline and at least 1 post-Baseline efficacy related assessment.
3.5.3
Pharmacokinetic Per Protocol Set
The PK-PPS will consist of all subjects from the SS having provided at least 1 measurable 
post-dose plasma sample (with recorded sampling time) on at least 1 visit with documented LCM 
intake times.
3.6
Treatment assignment and treatment groups
All subjects treated in this study receive LCM at doses ranging between 2mg/kg/day (or 
100 mg/day) to 12 mg/kg/day (or 600 mg/day). Summaries will be presented based on total 
number of subjects and will generally not be differentiated by LCM dose. Where appropriate, 
LCM dose will be presented on subject data listings.
3.7
Center pooling strategy
No data pooling strategies will be applied for analyses for this study. Unless otherwise stated, 
data from all sites will be combined and summarized collectively.
3.8
Coding dictionaries
Medical history and AEs will be coded using the Medical Dictionary for Regulatory Affairs 
(MedDRA®) Version 16.1. Medications and therapies will be coded using the World Health 
Organization Drug Dictionary (WHO-DD) version September 2013. Medical procedures will not 
be coded.
3.9
Changes to protocol-defined analyses
Not applicable.
4
STATISTICAL/ANALYTICAL ISSUES
4.1
Adjustments for covariates
Not applicable.
4.2
Handling of dropouts or missing data
4.2.1
Visit mapping in case of premature discontinuation
Subjects who prematurely discontinue the study will be evaluated based on the data collected at 
each visit attended. For these subjects, the early termination visit will be mapped to the next 
scheduled visit, ie, the assessments documented at Visit 9/ET will be assigned to the next 
scheduled visit, for which the corresponding assessment is scheduled, following the last 
documented visit.
4.2.2
Missing data
With respect to AEs, events with missing intensity will be assumed to be severe. Events with 
missing relationship to LCM per the investigator will be assumed to be related.
To assess the change and percent change in seizure days for any generalized seizures from the 
Baseline Period to the Maintenance Period for subjects who prematurely discontinue the study, a 
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 15 of 53
last observation carried forward convention will be applied in the following manner to obtain an 
estimate for the Maintenance Period:
!
Subjects discontinued prematurely during the Titration Period: estimates will be calculated 
using all available data in the Titration Period and carried forward for the Maintenance 
Period. 
!
Subjects discontinued prematurely during the Maintenance Period: estimates will be 
calculated using all available data in the Maintenance Period and carried forward for the 
entire Maintenance Period. 
!
Subjects completing the Maintenance Period: estimates will be calculated using all data from 
the Maintenance Period.
Missing values for other safety or preliminary efficacy variables will be not imputed. 
No imputation of missing values associated with an individual date or visit is planned, with the 
exception of partial date information for AEs and medications in order to determine whether they 
are treatment-emergent or concomitant, respectively, and for medical resources to define in 
which study period these were used. For details see Section 4.2.3.
4.2.3
Incomplete or missing dates for adverse events and concomitant 
medication
For analyses of AEs and concomitant medication usage, a complete date must be established in 
order to correctly identify the AE or medication as occurring during treatment in the study or not. 
For the purposes of imputing missing components of partially-reported start and stop dates for 
AEs and for medication use, the algorithms listed below will be followed. Start and stop dates of 
AEs or concomitant medication will be displayed as reported in the subject data listings (ie, no 
imputed values will be displayed in data listings).
!
Missing start day, but month and year present:
If the start of LCM occurred in the same month and year as the occurrence of the 
AE/concomitant medication, the start day of the event/concomitant medication will be 
assigned to the day of first administration of LCM.
Otherwise the start day will be set to the 1st day of the month.
!
Missing start day and month, but year present:
If the start of LCM occurred in the same year as the occurrence of the AE/concomitant 
medication, the start day and month will be assigned to the date of first administration of 
LCM.
Otherwise the start day and month will be set to January 1st.
!
Missing end day, but month and year present:
The end day will be set to the last day of the month.
!
Missing end day and month, but year present:
The end day and month will be set to the date of study termination or the date equivalent to 
30 days after last dose of LCM, whatever occurs later.
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 16 of 53
However, if the study termination year and year for the date which is 30 days after the last 
Dose of LCM are greater than the event/concomitant medication year, the day and month are 
to be set to December 31st.
An AE with a completely missing start date will be considered treatment-emergent if the end 
date of the AE is not on or before the date of first dose of LCM.
With respect to the definition of medication as concomitant, the following rule will be applied in 
case of completely missing stop and/or start date information:
Medications with a missing stop date and a start date prior to the date of last administration of 
LCM will be considered as concomitant medication. Medications with a missing start date whose 
stop date is either unknown or after the date of the first application of LCM will be considered as 
concomitant medication, but not as prior medication. Medications with missing start date whose 
stop date is prior to first administration of LCM will be considered as prior medication, but not 
as concomitant medication.
4.2.4
Incomplete dates for the last administration of LCM
For purposes of imputing missing components of partially reported dates for the last 
administration of LCM, the algorithms listed below will be followed. Stop dates of LCM will be 
displayed as reported in the subject data listings (ie, no imputed values will be displayed in data 
listing).
!
Missing last administration day, but month and year present:
The last administration day will be set to the last day of the month or the date of the final 
contact, whichever is earlier in the month.
!
Missing last administration day and month, but year present:
The last administration day will be set to the last day of the year or the date of the final 
contact, whichever is earlier in the year.
!
Completely missing date of last administration:
The last administration date will be imputed for the duration of exposure only as the date of 
last contact according to the study termination form. A review of the data will be performed 
to ensure that the imputation does not result in an unrealistic value for duration of exposure.
If a subject died during the study, and the imputed last administration date according to the rules 
above is after the date of death, the last administration date will be assigned to the date of death.
4.3
Interim analyses and data monitoring
No formal interim analysis is planned for this study; however, data will be presented to and 
reviewed by a DMC. The objectives and procedures for the DMC will be detailed in the DMC 
Charter.
4.4
Multicenter studies
Unless otherwise stated, descriptive summaries for individual sites will not be presented. Subject 
data listings will provide data grouped by site.
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 17 of 53
4.5
Multiple comparisons/multiplicity
There will be no adjustment for multiplicity in this study.
4.6
Use of an efficacy subset of subjects
Not applicable.
4.7
Active-control studies intended to show equivalence
Not applicable
4.8
Examination of subgroups
If not stated otherwise, summaries will be presented by age groups as given in Section 3.2.5. 
Separate age subgroupings are used for the purpose of summaries of questionnaires with 
different versions according to the age of the subject. Details are described in the corresponding 
sections describing the analysis of the questionnaires.
The following syndrome subgroups will be used to investigate AEs and seizure days: 
!
Infantile spasms/West syndrome
!
Lennox Gastaut syndrome
!
Dravet Syndrome
!
Other symptomatic generalized epilepsy
!
Primary generalized epilepsy
The classification of subjects to the syndromes will be done by a medical review and agreed 
during the DEM. Only subgroups with at least 4 subjects will be presented.
For the presentation of summaries by syndrome subgroups, the syndrome subgroups will be used 
instead of the age groups, ie, summaries will not be presented by syndrome and age group.
5
STUDY POPULATION CHARACTERISTICS
5.1
Subject disposition
The number of subjects screened, and the number and percentage of those subjects who were 
screen failures, broken down by primary reason for screening failure, will be presented for all 
subjects screened.
An overall summary of disposition for the SS will present the number and percentage of subjects 
completing the study and subjects discontinuing along with the reason for discontinuation. This 
summary will be presented overall as well as for the Titration Period and the Maintenance 
Period. The disposition summary will be repeated by syndrome subgroups (as described in 
Section 4.8).
The number and percentage of subjects who discontinued due to AEs broken down by type of 
AE will be presented overall only (ie, not by age group). The type of AE will be derived by 
combining outcome (fatal or not) and seriousness (serious or not) of all these AEs (for several 
AEs, if applicable) as given in the UCB Standard TFL Shells (see Table DS T 04). 
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 18 of 53
The date of first subject in, date of last subject out, number of screened subjects, and the number 
of subjects in each analysis set (SS, FAS, and PK-PPS) will be summarized overall and by site
for all subjects screened. Subjects who transferred sites will be summarized according to their 
original site. The summary by site will not be presented by age groups.
Additionally, the number and percentage of subjects in the different analysis sets (SS, FAS, and 
PK-PPS) will be provided.
5.2
Protocol deviations
Important protocol deviations defined in the SPD, and additionally identified at the DEM before 
database lock, will be listed for the SS. 
The number and percentage of subjects with at least 1 important protocol deviation will be 
summarized overall and by category of important protocol deviation for the SS. The number and 
percentage of subjects with no important protocol deviations will also be presented in this 
summary. This summary will not be presented by age group.
6
DEMOGRAPHICS AND OTHER BASELINE 
CHARACTERISTICS
6.1
Demographics
The BMI will be calculated using the formula
BMI = weight (kg) / (height (m))2.
The following demographics will be summarized for the SS:
!
Age (years) – continuous and categorized as (28 days - <24 months, 24 months - <12 years, 
12 years - <18 years)
!
Gender (male, female)
!
Race (American Indian/Alaskan Native, Asian, Black, Native Hawaiian or Other Pacific 
Islander, White, Other/Mixed)
!
Ethnicity (Hispanic or Latino, not Hispanic or Latino)
!
Height (cm)
!
Weight (kg)
!
BMI (kg/m2)
!
Head circumference (cm)
The demographics summary will be repeated by syndrome subgroups (as described in 
Section 4.8).
6.2
Other Baseline characteristics
The time since first diagnosis will be given in years (with 2 decimal places) and will be derived 
with the following formula:
(Date of informed consent - date of diagnosis) / 365.25
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 19 of 53
Partial dates will be imputed. If the month and year are available, the diagnosis date is imputed 
as the later of the following dates: the first day of the month, the subject’s birthdate, or the date 
of the first seizure (if available). If only a year is available, the later of the following dates will 
be imputed: January 1st of the year, the subject’s birthdate, and the date of the first seizure. 
Completely missing dates will not be replaced and the time since first diagnosis will be set to 
missing.
The age at first diagnosis will be derived using the same formula as age (see Section 3.2.5) but 
using the date of first diagnosis of disease instead of the date of informed consent. Partial dates 
of first diagnosis will be completed as described for the time since diagnosis. If the date of birth 
is incomplete, the age at first diagnosis will be derived as follows:
!
For subject with a partial date of birth with available information about year and month, use 
the first day of the month to impute the date of birth and use the imputed date of birth to 
calculate age at first diagnosis.
!
For subject with a partial date of birth with available information about year only, use age as 
given in the eCRF and subtract the time between (imputed) date of diagnosis and informed 
consent (ie, [date of informed consent – date of diagnosis] / 365.25).
Completely missing dates will not be replaced and the age at first diagnosis will be set to 
missing.
Antiepileptic drugs will be defined as medications documented on the “Concomitant 
Medications (AEDs only)” log form. A medical review will be performed to ensure that the 
medications are documented correctly. Corrective measurements (correction of documentation or 
programmatic mapping to the correct medication category [AED or not]) will be applied as 
applicable. Concomitant AEDs at Baseline will be defined as all concomitant AEDs given on the 
date of first dose of LCM. Medications will be counted only once per unique WHO-DD 
preferred name.
The following Baseline characteristics will be summarized for the SS:
!
Time since first diagnosis (years)
!
Age at diagnosis (years)
!
History of withdrawal seizures (yes, no)
!
History of status epilepticus (yes, no)
!
Number of concomitant AEDs at Baseline (1, 2, 3)
The ILAE Seizure classification (1981) history for the last 12 months will be summarized for the 
SS presenting number and percentage of subjects with the following categories:
!
Partial-onset seizures
∀
Simple partial with motor signs (I A1)
∀
Simple partial with somatosensory or special sensory symptoms (I A2) 
∀
Simple partial with autonomic symptoms or signs (I A3)
∀
Simple partial with psychic symptoms (I A4)
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 20 of 53
∀
Complex partial (I B)
∀
Partial evolving to secondarily generalized (I C) 
!
Generalized seizures
∀
Absence (II A) 
∀
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∀
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∀
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!
Unclassified epileptic seizures
∀
Unclassified epileptic seizures (III)
The historical seizure count form of the electronic Case Report form (eCRF) records the number 
of seizures per pre-selected ILAE seizure code experienced by the subject during the 4 weeks 
prior to the start of the study. These data will be provided in a subject data listing.
A listing of reproductive potential and birth control measures for female subjects will be 
provided.
6.3
Medical history and concomitant diseases
The number and percentage of subjects with a medical history condition, including both resolved 
and ongoing conditions at the time of study entry, will be summarized overall and by MedDRA®
primary system organ class (SOC) and preferred term (PT) for the SS.
6.4
Prior and concomitant medications
Medications will be considered as prior if the start date of the medication is before the date of 
first dose of LCM. Medications will be considered as concomitant if it was taken at least once 
during treatment with LCM (ie, from the date of first administration of LCM through the date of 
last administration of LCM). Medications starting prior to first dose of LCM and continuing 
during treatment with LCM will be considered both, prior and concomitant medication.
For cases of partial or missing dates the rules described in Section 4.2.3 will be applied.
The number and percentage of subjects taking concomitant AEDs will be summarized by 
WHO-DD chemical subgroup (Level 4) and preferred drug name for the SS. 
The number and percentage of subjects taking prior and concomitant medications (excluding 
AEDs) will be summarized separately by WHO-DD anatomical main group (Level 1) and 
therapeutic subgroup (Level 2) for the SS. 
Vagus nerve stimulation will only be listed.
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 21 of 53
7
MEASUREMENTS OF TREATMENT COMPLIANCE
7.1
Derivation of compliance
Actual weight of LCM oral solution will be calculated at each visit using the following formula:
Actual weight of used oral solution (g) = Total weight of bottles (including caps) at 
Dispensation - Total weight of bottles (including caps) at Return 
The actual weight used will also be determined for the Titration Period, Maintenance Period, and 
the entire Treatment Period by summing up the respective single actual weights. 
The following formula will be used to calculate the expected weight of oral solution for the 
respective LCM dose:
Expected weight of used oral solution (g) = Daily prescribed oral solution (mL) x Number of 
days between visits x 1.1g/mL. (The estimated weight of 1mL of LCM is 1.1g.)
The expected weight will also be determined for the Titration Period, Maintenance Period, and 
the entire Treatment Period by summing up the respective single expected weights. 
A subject’s dosing compliance should be within 75-125% during each visit. Compliance to LCM
dosing will be calculated for each visit, and will also be determined for the Titration Period, 
Maintenance Period, and the entire Treatment Period. 
For oral solution, compliance will be calculated using the following formula:
Compliance (%) = Actual weight of used oral solution (g) / Expected weight of used oral 
solution (g) x 100
For tablets, compliance will be calculated using the following formula:
Compliance (%) = (100 x [number of 100 mg tablets dispensed – number of 100 mg tablets 
returned] + 50 x [number of 50 mg tablets dispensed – number of 50 mg tablets returned]) / 
dose given on the Drug accountability form of the eCRF x number of days)) x 100
7.2
Presentation of compliance
Compliance will be summarized separately for the Treatment Period, the Titration Period and the 
Maintenance Period. It will be presented with descriptive statistics and additionally categorized 
as <75%, ≥75% to ≤125%, and >125% 
8
SAFETY ANALYSES
All safety analyses will be conducted for the SS.
8.1
Primary safety variables
8.1.1
Generalized spike-wave discharges
The actual values of generalized spike-wave discharges per interpretable hour on 24-hour 
ambulatory EEG as well as changes from Baseline will be summarized descriptively by visit.
Furthermore, a frequency table will be presented for the number of subjects with an increase of 
at least 30% and an increase of at least 50% at Visit 6 compared to Baseline.
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 22 of 53
8.1.2
Generalized seizures
Days with any generalized seizures per 28 days (GSD/28d) will be based on the seizure diary and 
will be derived separately for the Baseline Period, the Titration Period, and the Maintenance 
Period. Basis for the calculation will be the number of days with at least 1 generalized seizure 
(GSD) (absence, myoclonic, clonic, tonic, tonic clonic, atonic, partial evolving to secondarily 
generalized) during the considered study period and the number of days in the considered study 
period for which seizure information was provided (D):
GSD/28d = GSD x (28/D)
The days with any generalized seizures per 28 days will only be derived for subjects who 
completed or discontinued during the respective study period. For subjects who discontinued 
during the Titration Period, the missing value of the Maintenance Period will be imputed as 
described in Section 4.2.
Descriptive statistics will be provided for actual values and changes from Baseline for days with 
any generalized seizures per 28 days by study period. This summary will be repeated by 
syndrome subgroups (as described in Section 4.8).
8.2
Secondary safety variables
8.2.1
3Hz spike-wave discharges
The actual counts of 3Hz spike-wave discharges (during waking hours) on 24-hour ambulatory 
EEG as well as changes from Baseline will be summarized descriptively by visit.
Furthermore, a frequency table will be presented for the number of subjects with an increase of 
at least 30% and an increase of at least 50% at Visit 6 compared to Baseline.
8.2.2
Adverse events
Treatment-emergent AEs (TEAE) are defined as those events which start on or after the date of 
first LCM administration and within 30 days following the date of last LCM administration, or 
whose severity worsens within this time frame. 
Other significant AEs are defined in Appendix 13.1 (Table 13-1).
An overall summary of AEs will provide the numbers and percentages of subjects with at least 
1 TEAE, serious TEAE, other significant TEAE, TEAE that led to discontinuation, drug-related 
TEAE, drug-related serious TEAE, severe TEAE, AE leading to death, and TEAE leading to 
death. The AE overall summary will be repeated by syndrome subgroups (as described in 
Section 4.8).
The following summaries of AEs will be provided by primary SOC and PT:
!
TEAEs
!
TEAEs during the Titration Period
!
TEAEs during the Maintenance Period
!
TEAEs by syndrome subgroups (as described in Section 4.8)
!
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 23 of 53
!
Serious TEAEs
!
Serious TEAEs including subject numbers
!
TEAEs leading to discontinuation
!
TEAEs leading to discontinuation including subject numbers
!
TEAEs by maximum intensity
!
Nonserious TEAEs 
!
Nonserious TEAEs occurring in > 5% of subjects
!
Other significant TEAEs
The following summaries by primary SOC and PT will be presented overall only (ie, not by age 
group).
!
TEAEs by relationship to LCM
!
Serious TEAEs by relationship to LCM
!
Nonserious TEAEs by relationship to LCM
!
Fatal TEAEs by relationship to LCM
!
Nonserious TEAEs occurring in at least 5% of subjects by relationship
8.3
Exploratory safety variables
A frequency table will be presented for the number of subjects with a decrease of at least 30% 
and a decrease of at least 50% in generalized spike-wave discharges on 24-hour EEG at Visit 6 
compared to Baseline by syndrome subgroups
8.4
Extent of exposure
The duration of LCM exposure for each study period will be calculated as follows:
Duration of LCM (days) = date of last dose of LCM during the respective period minus the 
date of first dose of LCM during the respective period plus 1.
For the calculation of the mean daily dose during the Maintenance Period, the total dose for each 
entry in the LCM administration form with at least 1day within the Maintenance Period will be 
calculated as follows:
Total dose = (Morning dose + evening dose) x (administration stop date - administration start 
date + 1)
If the administration start date is before the start date of the Maintenance Period the start date of 
the Maintenance Period will be used instead. If the administration stop date is after the end date 
of the Maintenance Period the end date of the Maintenance Period will be used instead.
The mean daily dose during the Maintenance Period will be calculated as the sum of the total 
doses for each entry in the study medication administration form with at least 1 day within the 
Maintenance Period divided by the duration of LCM exposure during the Maintenance Period.
Days during an analysis period with unknown dosing will be excluded from both the numerator 
and the denominator for the calculation of the mean daily dose.
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 24 of 53
The mean daily dose will be presented in mg/kg/day. For patients who received tablets, the mean 
daily dose will be normalized by the baseline weight.
The duration of LCM exposure will be summarized with descriptive statistics overall (ie, for the 
entire Treatment Period) as well as separately for each study period (Titration Period, 
Maintenance Period). 
In addition, the duration of LCM exposure will be summarized in 14-day categories up to the 
scheduled duration of the period:
!
Treatment Period: ≤14 days, >14-≤28 days, >28-≤42 days, >42-≤56 days, >56-≤70 days, 
>70-≤84 days, >84-≤98 days, >98-≤112 days, >112-≤126 days, >126-≤140 days, 
>140-≤154 days, >154-≤168 days, and >168 days. 
!
Titration Period: ≤14 days, >14-≤28 days, >28-≤42 days, and >42 days.
!
Maintenance Period: ≤14 days, >14-≤28 days, >28-≤42 days, >42-≤56 days, >56-≤70 days, 
>70-≤84 days, and >84 days. 
The mean daily dose during the Maintenance Period will be summarized descriptively.
8.5
Clinical laboratory evaluations
The following laboratory parameters are measured within the study:
!
Hematology: red blood cell count, white blood cell count, differential count (lymphocytes, 
basophils, eosinophils, monocytes, neutrophils), platelet count, hematocrit, and hemoglobin
!
Chemistry: calcium, serum electrolytes (sodium, potassium, chloride, bicarbonate), total 
protein, albumin, phosphate, glucose, uric acid, alkaline phosphatase, urea nitrogen, 
creatinine, aspartate aminotransferase, alanine aminotransferase, gamma glutamyltransferase, 
total bilirubin, cholesterol, triglycerides
!
Urinalysis: albumin, specific gravity, ketones, glucose, pH, microscopic exam for blood cells 
or casts/high power field
!
Endocrinology: FSH, LH, T3, T4, TSH
Markedly abnormal laboratory values are defined in appendix 13.2. Treatment-emergent 
markedly abnormal (TEMA) values are defined as those markedly abnormal values which occur 
during the Treatment Period (including unscheduled visits), ie, with a normal Baseline value.
Observed values and changes from Baseline will be summarized for the parameters of 
hematology, chemistry and endocrinology given above. The Last Visit and minimum and 
maximum post-Baseline values during the Treatment Period will also be presented in these 
summaries. Repeated or unscheduled laboratory assessments during the study will not be 
presented in the by-visit summaries, but will be considered when determining the Last Visit, 
minimum post-Baseline value, and maximum post-Baseline value.
The number and percentage of subjects with a TEMA value, TEMA low value, and TEMA high 
value will be summarized by parameter and visit. Percentages will be based on the number of 
subjects with a nonmissing value at the respective visit. Additionally, a list of subjects with at 
least 1 TEMA value will be provided including all laboratory measurements of the respective 
parameter of the respective subject.
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 25 of 53
Urinalysis and pregnancy test results will only be listed.
8.6
Vital signs, physical findings, and other observations related to 
safety
8.6.1
Vital signs, body weight, height, BMI, and head circumference
Markedly abnormal vital signs values are defined in Table 8‒1. 
Table 8‒1:
Vital Signs Abnormality Criteria
Parameter
Age Range
Abnormality Criteria
Pulse Rate (beats/minute)
<6m
<100, >180
6m - <3y
<90, >150
3y - <12y
<60, >130
12y - <17y
≤50, ≥120
≥17y
≤50 and a decrease from Baseline of ≥15
≥120 and an increase from Baseline of ≥15
Systolic BP (mmHg)
<6m
<60, >100
6m - <3y
<70, >120
3y - <12y
<80, >140
12y - <17y
<90, >160
≥17y
≤90 and a decrease from Baseline of ≥20
≥180 and an increase from Baseline of ≥20
Diastolic BP (mmHg)
<6m
<40, >65
6m - <3y
<45, >75
3y - <12y
≤50, ≥80
12y - <17y
≤50, ≥105
≥17y
≤50 and a decrease from Baseline of ≥15
≥105 and an increase from Baseline of ≥15
Temperature
All
>101 0F (38.3 0C)
Body Weight
1 month - <17y
<3% or >97% of the normal body weight
growth curve ranges1 based on gender and the
age of subject on date of weight assessment
≥17y
≥10% change from Baseline (an increase or a
decrease)
1 source: http://www.cdc.gov/growthcharts/html_charts/wtage.htm
BP=blood pressure, m=month, y=year. 
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 26 of 53
Observed values and changes from Baseline for vital signs (systolic BP, diastolic BP, and pulse 
rate) will be summarized by visit and position/time point including the Last Visit.
Changes of standing measurements versus supine measurements of systolic BP, diastolic BP, and 
pulse rate will also be summarized for each visit and time point including the Last Visit.
Observed values and changes from Baseline for body weight, height, BMI, and head 
circumference will be summarized by visit. The Last Visit will also be presented in this 
summary.
The number and percentage of subjects with a markedly abnormal value, markedly abnormal low 
value, and markedly abnormal high value will be presented by visit. Percentages will be based on 
the number of subjects with a nonmissing value at the respective visit. Additionally, a list of 
subjects with at least 1 markedly abnormal value will be provided including all vital sign 
measurements of the respective subject.
8.6.2
Electrocardiograms
Abnormality criteria to be used in the determination of ECG abnormalities are defined in 
Table 8‒2, where increase and decrease are relative to Baseline values:
Table 8‒2:
Electrocardiogram Abnormality Criteria
Parameter
Age Range
Abnormality Criteria
QT interval (ms)
1m-<12y
≥500
≥12y
≥500 or ≥60ms increase from Baseline
QTc(F) (ms)
<6m
>490, or >15% increase from Baseline
6m-<17y
>440, or >15% increase from Baseline
≥17y
≥500 or ≥60ms increase from Baseline
QTc(B) (ms)
<6m
>490, or >15% increase from Baseline
6m-<17y
>450, or >15% increase from Baseline
≥17y
≥500 or ≥60ms increase from Baseline
PR interval (ms)
<6m
>150, or ≥25% increase from Baseline
6m-<3y
>170, or ≥25% increase from Baseline
3y-<12y
>180, or ≥25% increase from Baseline
≥12y - <17y
>200, or ≥25% increase from Baseline
≥17y
Treatment-emergent value >200, >220, >250
QRS interval (ms)
1m-<3y
>90, or ≥25% increase from Baseline
3y-<12y
>100, or ≥25% increase from Baseline
≥12y - <17y
≥110, or ≥25% increase from Baseline
≥17y
Treatment-emergent value >100, >120, >140
Heart rate (bpm)
<6m
<100, >180
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 27 of 53
Table 8‒2:
Electrocardiogram Abnormality Criteria
Parameter
Age Range
Abnormality Criteria
6m-<3y
<90, >130
3y-<12y
<60, >130
>12y
<50, >120
bpm=beats per minute; m=months; ms=milliseconds; QTc=corrected QT interval; y=years. 
A month is defined as 30 days; a year is defined as 365.25 days.
Treatment-emergent ECG abnormalities are defined as values meeting the criteria given in 
Table 8‒2 at any post-Baseline visit during the Treatment Period (including unscheduled visits) 
and not meeting the same criteria during Baseline.
For ECGs, baseline will be defined as the average of all pre-dose interpretable readings. For all 
post-baseline visits, the average of all interpretable readings at the specified visit will be used for 
summaries.
Observed results and changes from Baseline in ECG results will be summarized for all visits and 
the Last Visit.
The number and percentage of subjects with no abnormality, an abnormal but not clinically 
significant finding, and a clinically significant finding, will be summarized by visit, including 
last visit. Percentages will be relative to the number of subjects with an ECG assessment at the 
respective visit. Subjects are counted once at each visit based on the worst observed outcome 
across all abnormalities reported at that visit.
Summaries of shifts from Baseline to post-Baseline visits (including Last Visit) will also be 
provided based on the categories normal, abnormal, not clinically significant, and abnormal, 
clinically significant.
The number and percentage of subjects with treatment-emergent ECG abnormalities will be 
presented by visit and treatment group. Abnormalities reported at an unscheduled visit will be 
summarized under the scheduled visit preceding the unscheduled visit (if the abnormality was 
not present already at the preceding scheduled visit). Percentages will be based on the number of
nonmissing values for the variable and visit. In addition, a listing including all ECG parameter 
values for subjects meeting any abnormality criteria will be provided.
8.6.3
Physical and neurological examination
Summaries of shift from Baseline to Visit 9/ET will be provided based on categories normal, 
abnormal, not clinically significant, and abnormal, clinically significant for each of the single 
neurological examinations. Summaries of shift from Baseline normal to any post-baseline 
abnormal, clinically significant category for each of the neurological examinations will also be 
provided. For physical examination, summaries of shift from Baseline normal to any post-
baseline abnormal, clinically significant category will be presented. 
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06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 28 of 53
8.6.4
Tanner stage assessment
The Tanner stage is a measurement for the subject’s sexual development used for subjects 
pubescent at Visit 1. It is a 3-item scale (for females: breasts, pubic hair, and overall stage; and 
for males: genitals, pubic hair, and overall stage) with 5 possible stages (I, II, III, IV, or V).
Shift tables will be produced showing the change in Tanner stage from Visit 1 to Visit 9/ET by 
gender for each of the 3 single items. Percentages will be based on the number of subjects with at 
least 1 nonmissing value at Visit 1 or Visit 9/ET. 
8.6.5
Achenbach Child Behavior Checklist
The Achenbach CBCL is a questionnaire intended to evaluate a child’s competencies and 
behavioral/emotional problems. Depending on the subject’s age, 1 of 2 versions of the 
Achenbach CBCL is used. The CBCL/1½-5 is intended for use in children 18 months to 5 years 
and 11 months of age at Baseline. For subjects ≥6 years to <18 years at Baseline, the CBCL/6-18 
will be used. For each subject, the same version that is used at Visit 2 (Baseline) should be used 
at all following visits.
The CBCL/1½-5 comprises 100 questions and the CBCL/6-18 comprises 120 questions with the 
response options of: 
!
0=not true (as far as known)
!
1=somewhat or sometimes true
!
2=very true or often true
The CBCL/1½-5 will be grouped according to syndrome scales as given in Table 8‒1.
Table 8‒1:
CBCL/1½-5 
Syndrome scale
Questions
Aggressive behavior
8, 15, 16, 18, 20, 27, 29, 35, 40, 42, 44, 53, 58, 66, 69, 81, 85, 88, 96
Anxious/depressed
10, 33, 37, 43, 47, 68, 87, 90
Attention problems
5, 6, 56, 59, 95
Emotionally reactive
21, 46, 51, 79, 82, 83, 92, 97, 99
Sleep problems
22, 38, 48, 64, 74, 84, 94
Somatic complaints
1, 7, 12, 19, 24, 39, 45, 52, 78, 86, 93
Withdrawn
2, 4, 23, 62, 67, 70, 71, 98
Other problems
3, 9, 11, 13, 14, 17, 25, 26, 28, 30, 31, 32, 34, 36, 41, 49, 50, 54, 55, 57, 
60, 61, 63, 65, 72, 73, 75, 76, 77, 80, 89, 91, 100
The CBCL/6-18 will be grouped according to empirically based syndrome scales as given in 
Table 8‒2.
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 29 of 53
Table 8‒2:
CBCL/6-18 
Syndrome scale
Questions
Aggressive behavior
3, 16, 19, 20, 21, 22, 23, 37, 57, 68, 86, 87, 88, 89, 94, 95, 97, 104
Anxious/depressed
14, 29, 30, 31, 32, 33, 35, 45, 50, 52, 71, 91, 112
Attention problems
1, 4, 8, 10, 13, 17, 41, 61, 78, 80
Rule-breaking behavior
2, 26, 28, 39, 43, 63, 67, 72, 73, 81, 82, 90, 96, 99, 101, 105, 106
Social problems
11, 12, 25, 27, 34, 36, 38, 48, 62, 64, 79
Somatic complaints
47, 49, 51, 54, 56a, 56b, 56c, 56d, 56e, 56f, 56g, 
Thought problems
9, 18, 40, 46, 58, 59, 60, 66, 70, 76, 83, 84, 85, 92, 100
Withdrawn/depressed
5, 42, 65, 69, 75, 102, 103, 111
Standardized T-scores are determined for each subject’s raw syndrome and overall scores based 
on the subject’s age and sex. Tables mapping each raw score to the appropriate T-score are 
provided in the CBCL Professional Manual and will be reproduced programmatically. 
For each questionnaire (CBCL/1½-5 and CBCL/6-18, respectively), calculated T-score values 
and change from Baseline for each CBCL syndrome as given in Table 8‒1 and Table 8‒2, 
respectively, will be summarized by visit. The summaries will be presented by the 
questionnaire’s age groups (18 months to 5 years and ≥6 years to <18 years) instead of the ones 
defined in Section 3.2.5.
8.6.6
BRIEF-P and BRIEF assessment
The BRIEF-P and BRIEF are validated tools that will be used for the evaluation of subjects ≥2 to 
<5 years of age, and ≥5 years of age, respectively. For each subject, the same version (BRIEF-P 
or BRIEF) that is used at Visit 2 (Baseline) should be used at Visit 9/ET.
8.6.6.1
BRIEF-P scores
The BRIEF-P form comprises 63 questions with entry options N (never: scored as 1 point), 
S (sometimes: scored as 2 points), and O (often: scored as 3 points).
The 63 items sum up to the raw Global Executive Composite (GEC) score which ranges from 63 
to 189. Higher scores are reflecting poorer functioning.
The 3 subscale scores and 5 individual component scores that make up these subscale scores are 
outlined in Table 8‒3.
Table 8‒3:
BRIEF-P questionnaire scoring
Scale/Index
Questions
Inhibit
3, 8, 13, 18, 23, 28, 33, 38, 43, 48, 52, 54, 56, 58, 60, 62
Shift
5,10, 15, 20, 25, 30, 35, 40, 45, 50
Emotional Control
1, 6, 11, 16, 21, 26, 31, 36, 41, 46
Inhibitory self-control
All from {Inhibit and Emotional Control}
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 30 of 53
Table 8‒3:
BRIEF-P questionnaire scoring
Scale/Index
Questions
Flexibility
All from {Shift and Emotional Control}
Working Memory
2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 51, 53, 55, 57, 59, 61, 63
Plan/Organize
4, 9, 14, 19, 24, 29, 34, 39, 44, 49
MI
All from {Working Memory and Plan/Organize}
GEC Score
1-63
MI=Metacognition Index, GEC=Global Executive Composite
Standardized T-scores are determined from each subject’s raw GEC, Behavioral Regulation 
Index (BRI), Metacognition Index (MI), and component scores based on the subject’s age and 
sex. Tables that map each raw score to the appropriate T-score are provided in the BRIEF-P 
Professional Manual and will be reproduced programmatically.
Calculated T-score values and change from Baseline for the 2 indexed scores (BRI and MI), and 
GEC for the BRIEF-P questionnaire will be summarized by visit for the respective age group (≥2 
to <5 years), ie, the age groups as defined in Section 3.2.5 will not be used.
8.6.6.2
BRIEF scores
The BRIEF form comprises 86 questions with entry options N (never: scored as 1 point), 
S (sometimes: scored as 2 points), and O (often: scored as 3 points).
The first 72 items sum up in the GEC score which ranges from 72 to 216, with higher scores 
reflecting poorer functioning.
The 2 subscale scores and 8 individual component scores that make up these subscale scores are 
outlined in Table 8‒4.
Table 8‒4:
BRIEF questionnaire scoring
Scale/Index
Questions
Inhibit
38, 41, 43, 44, 49, 54, 55, 56, 59, 65
Shift
5, 6, 8, 12, 13, 23, 30, 39
Emotional Control
1, 7, 20, 25, 26, 45, 50, 62, 64, 70
BRI
All from {Inhibit, Shift, and Emotional Control}
Initiate
3, 10, 16, 47, 48, 61, 66, 71
Working Memory
2, 9, 17, 19, 24, 27, 32, 33, 37, 57
Plan/Organize
11, 15, 18, 22, 28, 35, 36, 40, 46, 51, 53, 58
Organization of Materials
4, 29, 67, 68, 69, 72
Monitor
14, 21, 31, 34, 42, 52, 60, 63
MI
All from {Initiate, Working Memory, Plan/Organize, 
Organization of Materials, and Monitor}
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 31 of 53
Table 8‒4:
BRIEF questionnaire scoring
Scale/Index
Questions
GEC Score
1-72
BRI=Behavioral Regulation Index, MI=Metacognition Index, GEC=Global Executive Composite
Standardized T-scores are determined from each subject’s raw GEC, BRI, MI, and component 
scores based on the subject’s age and sex. Tables that map each raw score to the appropriate 
T-score are provided in the BRIEF Professional Manual and will be reproduced 
programmatically.
Calculated T-score values and change from Baseline for the 2 indexed scores (BRI and MI), and 
GEC for the BRIEF questionnaire will be summarized by visit for the respective age group 
(≥5 years), ie, the age groups as defined in Section 3.2.5 will not be used.
9
ANALYSES OF EFFICACY VARIABLES
All analyses of preliminary efficacy variables will be conducted for the FAS.
9.1
Preliminary Efficacy Variables
9.1.1
Seizure days
Days with seizures per 28 days for each seizure type and study period will be calculated as 
described for the generalized seizures in Section 8.1.2.
Percent change in seizure days is calculated as the respective seizure days per 28 days during the 
respective period (Titration Period and Maintenance Period) minus respective seizure days per 
28 days during the Baseline Period divided by seizure days per 28 days during the Baseline 
Period and then multiplied by 100. 
Descriptive statistics will be used to summarize the observed values as well as absolute and 
percent changes from Baseline in seizure days per 28 days by study period (Baseline, Titration,
and Maintenance Period, respectively). Summaries will be provided for the following seizure 
types:
!
Any generalized seizures (absence, myoclonic, clonic, tonic, tonic-clonic, atonic, partial 
evolving to secondarily generalized) 
!
Absence seizures
!
Myoclonic seizures
!
Clonic seizures 
!
Tonic seizures
!
Tonic-clonic seizures
!
Atonic seizures
9.1.2
Clinical global impression of change
The Clinical Global Impression of Change is a 7-point categorical rating scale in which the 
investigator assesses the subject’s change from Baseline in clinical status.
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 32 of 53
The number and percentage of subjects for each possible response of the Clinical Global 
Impression of Change will be presented. In addition, the 3 improvement values (very much 
improved, much improved, and minimally improved) grouped as “Improved” and the 3 
worsening values (minimally worse, much worse, and very much worse) grouped as 
“Worsened”, as well as the “No change” group will be summarized in the same way. Percentages 
will be based on the number of subjects with nonmissing values.
9.1.3
Caregiver’s global impression of change
The Caregiver’s Global Impression of Change is a 7-point categorical rating scale in which the 
caregiver assesses the subject’s change from Baseline in clinical status.
The number and percentage of subjects for each possible response of the Caregiver’s Global 
Impression of Change will be presented. In addition, the 3 improvement values (very much 
improved, much improved, and minimally improved) grouped as “Improved” and the 3 
worsening values (minimally worse, much worse, and very much worse) grouped as 
“Worsened”, as well as the “No change” group will be summarized in the same way. Percentages 
will be based on the number of subjects with nonmissing values.
9.1.4
Pediatric quality of life inventory
The PedsQL is a validated instrument that consists of generic core scales suitable for use with 
pediatric populations, including those with acute or chronic health conditions. The PedsQL 
Measurement Model consists of developmentally appropriate forms for pediatric subjects 
≥1 month to ≤12 months; ≥13 months to ≤24 months; >2 years to ≤4 years, ≥5 years to ≤7 years, 
≥8 years to ≤12 years, and ≥13 years to ≤18 years of age. For each subject, the same version that 
is used at Visit 2 (Baseline) should be used at Visit 9/ET.
PedsQL generic core scale scores will be calculated for each of the following 4 PedsQL scales:
!
Physical Functioning
!
Emotional Functioning
!
Social Functioning
!
School Functioning 
The PedsQL assessment is retrospective to the prior 4 weeks, and individual items are scored 
using a 5-point Likert scale (0 to 4 representing responses of: never, almost never, sometimes, 
often, or almost always). These scores of 0 to 4 will be transformed by the function: 100 –
(response x 25) in order to generate scores of 0, 25, 50, 75, and 100 where a higher value 
represents a better health-related quality of life. 
Each scale score is then calculated as the mean of the corresponding nonmissing items if 50% or 
more of the items are nonmissing. The same algorithm will be used to calculate an overall Total 
Scale Score (all scales) and the Psychosocial Health Summary Score (a combination of the 
emotional, social and school functioning questions) for each subject.
Calculated values and change from Baseline for the total scale score and each of the 4 scale 
scores will be summarized by visit. For the presentation of the PedsQL summary, the 
questionnaire’s age groups (≥1 month to ≤12 months, ≥13 months to ≤24 months, ≥2 to ≤4 years, 
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 33 of 53
≥5 to ≤7 years, ≥8 to ≤12 years, and ≥13 to ≤18 years) will be used instead of the ones defined in
Section 3.2.5.
9.1.5
Health care resource use
To assign the health resources to a specific study period (Baseline, Titration, and Maintenance, 
respectively), partial or missing dates will be imputed as described for AEs and concomitant 
medications in Section 4.2.3. Hospital stays will be attributed to study periods based on the 
admission date. 
An event logged on the Hospitalization/ER Visit form of the eCRF where “Emergency room” is 
marked as initial entry point will be defined as an emergency room (ER) visit. An ER visit with a 
subject transfer to an inpatient general ward will also be counted as a hospitalization. However, 
all other instances of ER visits (where subject transfer is not to an inpatient general ward) will 
not be counted as hospitalizations.
For hospital stays with a discharge date, the duration of each hospital stay will be calculated as 
the discharge date minus the admission date (Hospitalization/ER Visit Date on the eCRF) plus 
1 day. For hospitalizations with either a partial admission or discharge date, the duration of 
hospital stay will be set to missing. The nonmissing durations of hospital stays will be summed 
within each of the study periods (Baseline, Titration, and Maintenance, respectively). Should 
distinct records for hospital stays overlap, then the days during the overlap will only be counted 
once. Subjects with no hospital stays within a study period will have duration of 0 days for that 
period. For subjects with hospital stays but no calculable hospital duration, the duration of 
hospitalization in the respective study period will be missing.
The number of concomitant medical procedures per subject (number of entries in the 
concomitant procedure form) will be summarized continuously and in categories (0, 1, 2, and 3 
or more) for the Baseline Period, the Titration Period, and the Maintenance Period. 
The number of healthcare provider consultations per subject will be summarized continuously 
and in categories (0, 1, 2, 3, 4, and 5 or more) for the Baseline Period, the Titration Period, and 
the Maintenance Period. In addition, the number and percentage of subjects with at least 
1 consultation will be given for general practitioner, specialist physician, nurse, or other by study 
period.
The number of hospital stays per subject will be summarized continuously and in categories (0, 
1, 2, 3, 4, and 5 or more) for the Baseline Period, the Titration Period, and the Maintenance 
Period. The number and percentage of subjects with specific reasons for a hospital stay (epilepsy, 
lack of efficacy, AE, elective procedure, and other) will also be summarized for these study 
periods. Furthermore, the duration of hospital stays will be summarized in categories (0 days, 1
to 5 days, 6 to 10 days, 11 to 15 days, and >15 days) by study period. Descriptive statistics for 
the number of ER visits within each study period will be presented. These summaries will be 
repeated by syndrome subgroups (as described in Section 4.8).
9.2
Exploratory  Efficacy Variables
The analysis of the exploratory efficacy variable will be conducted for the FAS.
Days with seizures per 28 days for each seizure type and study period will be calculated as 
described for the generalized seizures in Section 8.1.2. The days with any generalized seizures 
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 34 of 53
per 28 days will only be derived for subjects who completed or discontinued during the 
respective study period. For subjects who discontinued during the Titration period, the missing 
value of the maintenance period will be implemented as described in Section 4.2
Descriptive statistics will be used to summarize the proportion of subjects who have at least a 50 
percent reduction in generalized seizures per 28 days by study period (Titration and Maintenance 
Period) and syndrome subgroup.
Descriptive statistics will also be produced to summarize the proportion of subjects who have 
more than 30% and 50% increase in generalized seizures per 28 days during the study period
(Titration and Maintenance Period) by syndrome subgroup.
Descriptive statistics will be produced to summarize the percent change in days with any 
generalized seizures per 28 days during the study period by syndrome subgroup.
10
PHARMACOKINETICS
10.1
Descriptive statistics of LCM and AED plasma concentrations
The results of LCM plasma concentrations will be described by the method of descriptive 
statistics: n, >=limit of quantification (LOQ), arithmetic mean, SD, median,  geometric mean, 
and geometric CV. Summary statistics will only be calculated if at least 2/3 of the data are above 
the lower LOQ. Values <LOQ will be set to LOQ/2 for the determination of summary statistics.
The summary of LCM plasma concentrations will be presented by dose level during the 
Maintenance Period (dose with the longest duration during the Maintenance Period) and visit.
The dose levels will be combined as 4-6 mg/kg/day, 7-8 mg/kg/day, 9-10 mg/kg/day, and 11-12 
mg/kg/day.
Other AED plasma concentrations will only be listed.
10.2
Population pharmacokinetics and exposure response
Population pharmacokinetics and exposure-response modeling are not in the scope of the SAP 
and will be described in separate data analysis plans.
11
OTHER ANALYSES 
Data of Bayley Scales of Infant and Toddler Development®, Third Edition (Bayley-III) and 
Columbia-Suicide Severity Rating Scale will only be listed. The analysis of the Bayley-III scales 
data will be performed in the follow-up study, SP848.
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 35 of 53
12
REFERENCES
Not applicable.
COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 36 of 53
13
APPENDICES
13.1
Significant Adverse Events
Table 13-1: List of other significant AEs
MedDRA Preferred Term
HEPATOTOXICITY RELATED TERMS
Hepatitis toxic
Hepatotoxicity
Drug-induced liver injury
Liver function test abnormal
Alanine aminotransferase increased
Aspartate aminotransferase increased
CARDIAC AND ECG RELATED TERMS
Atrioventricular block complete
Atrioventricular block second degree
Bradyarrhythmia*
Bradycardia*
Cardiac pacemaker insertion
Atrial fibrillation
Atrial flutter
Sinus bradycardia*
Ventricular tachycardia
Ventricular fibrillation
Heart Rate decreased*
Sick sinus syndrome
SUICIDALITY RELATED TERMS
Completed suicide
Depression suicidal
Suicidal behaviour
Suicidal ideation
Suicide attempt
Intentional self-injury
Self injurious behaviour
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 37 of 53
Table 13-1: List of other significant AEs
MedDRA Preferred Term
Self-injurious ideation
Intentional overdose
Poisoning deliberate
ADDITIONAL TERMS
Loss of consciousness
Syncope
* All cases with reported reduced heart rate will be reviewed and only cases with marked bradycardia (marked 
reduction in heart rate) with HR <45 bpm will be listed as ‘Other Significant AEs’.
13.2
Marked abnormality criteria for laboratory data
13.2.1
Marked abnormality criteria for hematology data
Table 13‒2: Hematology abnormality criteria
Parameter
Age Range
Unit 
(conventional)
Abnormality 
criteria 
(conventional 
unit)
Unit 
(standard)
Abnormality 
criteria 
(standard 
unit)
Hematocrit
<2y
%
≤27
>45
%
≤27
>45
2y - <17y
%
≤29
>47
%
≤29
>47
≥17y
%
≤85% of LLN
≥115% of ULN
%
≤85% of LLN
≥115% of ULN
Hemoglobin
<2y
g/dL
≤9.0
>15.0
g/L
≤90
>150
2y - <17y
g/dL
≤9.5
>16.0
g/L
≤95
>160
≥17y
g/dL
≤85% of LLN
≥115% of ULN
g/L
≤85% of LLN
≥115% of ULN
WBC/ 
Leukocytes
All
109/L
≤3.0
≥16.0
G/L
≤3.0
≥16.0
Lymphocytes 
Absolute
<2y
109/L
<1.0
>9.8
G/L
<1.0
>9.8
2y - <6y
109/L
<0.7
>6.9
G/L
<0.7
>6.9
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 38 of 53
Table 13‒2: Hematology abnormality criteria
Parameter
Age Range
Unit 
(conventional)
Abnormality 
criteria 
(conventional 
unit)
Unit 
(standard)
Abnormality 
criteria 
(standard 
unit)
≥6y
109/L
<0.6
>5.0
G/L
<0.6
>5.0
Basophils
>1m
%
≥5.0
%
≥5.0
Basophils 
Absolute
>1m
109/L
≥0.4
G/L
≥0.4
Eosinophils
>1m
%
≥10
%
≥10
Eosinophils 
Absolute
>1m
109/L
≥1.0
G/L
≥1.0
Monocytes
>1m
%
≥20.0
%
≥20.0
Monocytes 
Absolute
>1m
109/L
≥2.0
G/L
≥2.0
Neutrophils 
Absolute
>1m
109/L
<1.5
G/L
<1.5
Platelets
>1m
109/L
≤100
≥600
G/L
≤100
≥600
RBC/ 
Erythrocytes
<2y
1012/L
<3.0
T/L
<3.0
≥2y
1012/L
<3.5
T/L
<3.5
LLN=lower limit of normal, m=month, RBC=red blood cells, ULN=upper limit of normal, WBC=white blood cells, 
y=year. 
A month is defined as 30 days; a year is defined as 365.25 days.
13.2.2
Marked abnormality criteria for chemistry data
Table 13‒3: Chemistry abnormality criteria
Parameter
Age Range
Unit 
(conventional)
Abnormality 
criteria 
(conventional 
unit)
Unit 
(standard)
Abnormality 
criteria 
(standard 
unit)
AST (SGOT)
All
U/L
≥3.0 x ULN
≥5.0 x ULN
≥10.0 x ULN
U/L
≥3.0 x ULN
≥5.0 x ULN
≥10.0 x ULN
ALT (SGPT)
All
U/L
≥3.0 x ULN
≥5.0 x ULN
≥10.0 x ULN
U/L
≥3.0 x ULN
≥5.0 x ULN
≥10.0 x ULN
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 39 of 53
Table 13‒3: Chemistry abnormality criteria
Parameter
Age Range
Unit 
(conventional)
Abnormality 
criteria 
(conventional 
unit)
Unit 
(standard)
Abnormality 
criteria 
(standard 
unit)
Alkaline 
Phosphatase
<4y
U/L
≥690
U/L
≥690
4y - <10y
U/L
≥834
U/L
≥834
10y - <17y
U/L
≥1761
U/L
≥1761
≥17y
U/L
≥3.0 x ULN
U/L
≥3.0 x ULN
GGT
<6m
U/L
≥522
U/L
≥522
6m - <1y
U/L
≥279
U/L
≥279
1y - <13y
U/L
≥66
U/L
≥66
13y - <17y
U/L
≥126
U/L
≥126
≥17y
U/L
≥3.0 x ULN
U/L
≥3.0 x ULN
Total Bilirubin
>1m
mg/dL
≥2.0
umol/L
≥34.208
Total Protein
2m-<1y
g/dL
<3.0
>11.9
g/L
<30
>119
1y - <17y
g/dL
<4.3
>12.0
g/L
<43
>120
≥17y
g/dL
<4.3
>13.0
g/L
<43
>130
Albumin
<1y
g/dL
<1.6
>7.2
g/L
<16
>72
≥1y - <17y
g/dL
<2.4
>8.4
g/L
<24
>84
≥17y
g/dL
<2.6
g/L
<26
BUN
<1y
mg/dL
≥24
mmol/L
≥8.568
1y - <17y
mg/dL
≥36
mmol/L
≥12.852
≥17y
mg/dL
≥40
mmol/L
≥14.28
Creatinine
1y - <10y
mg/dL
>1.2
umol/L
>106.8
10y - <16y
mg/dL
>1.8
umol/L
>159.12
≥16y
mg/dL
≥2.0
umol/L
≥176.8
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 40 of 53
Table 13‒3: Chemistry abnormality criteria
Parameter
Age Range
Unit 
(conventional)
Abnormality 
criteria 
(conventional 
unit)
Unit 
(standard)
Abnormality 
criteria 
(standard 
unit)
Bicarbonate
>1m - <17y
mEq/L
<15
>38
mmol/L
<15
>38
≥17y
mEq/L
<18
>38
mmol/L
<18
>38
Calcium
<1y
mg/dL
<6.9
>12.2
mmol/L
<1.725
>3.05
1y - <17y
mg/dL
<7.4
>11.7
mmol/L
<1.85
>2.925
≥17y
mg/dL
≤7.6
≥11.0
mmol/L
≤1.9
≥2.75
Chloride
>1m
mEq/L
≤90
≥112
mmol/L
≤90
≥112
Phosphorous
<1y
mg/dL
<1.8
>8.2
mmol/L
<0.5814
>2.6486
1y - <17y
mg/dL
<1.8
>7.4
mmol/L
<0.5814
>2.3902
≥17y
mg/dL
≤2.0
≥6.0
mmol/L
≤0.646
≥1.938
Potassium
<1y
mEq/L
≤3.0
≥6.5
mmol/L
≤3.0
≥6.5
≥1y
mEq/L
≤3.0
≥6.0
mmol/L
≤3.0
≥6.0
Sodium
>1m
mEq/L
<127
>151
mmol/L
<127
>151
Glucose
>1m - <17y
mg/dL
<50
≥180
mmol/L
<2.775
≥9.99
≥17y
mg/dL
<50
≥200
mmol/L
<2.775
≥11.1
Total 
Cholesterol
≥1y
mg/dL
>250
mmol/L
>6.475
Triglycerides
<1y
mg/dL
>750
mmol/L
>8.475
≥1y
mg/dL
>300
mmol/L
>3.39
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 41 of 53
Table 13‒3: Chemistry abnormality criteria
Parameter
Age Range
Unit 
(conventional)
Abnormality 
criteria 
(conventional 
unit)
Unit 
(standard)
Abnormality 
criteria 
(standard 
unit)
Uric Acid
<1y
mg/dL
>7.7
umol/L
>457.996
1y - <13y
mg/dL
>6.5
umol/L
>386.62
13y - <17y
mg/dL
>8.6
umol/L
>511.528
≥17y
mg/dL
>9.5
umol/L
>565.06
Thyroxine (T4)
<1y
ug/dL
≤4.3
≥18.4
nmol/L
≤55.3453
≥236.8264
≥1y
ug/dL
≤3.8
≥13.5
nmol/L
≤48.9098
≥173.7585
ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; dL=deciliter; 
GGT=gamma-glutamyltransferase; HDL=high density lipoprotein; LDL=low density lipoprotein; L=liter; 
m=month (a month is defined as 30 days); mg=milligram; mmol=millimoles; μg=microgram; U=unit; ULN=upper 
limit of normal; y=years (a year is defined as 365.25 days)
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 42 of 53
14
AMENDMENT(S) TO THE STATISTICAL ANALYSIS PLAN 
(SAP)
14.1
Amendment 1
Rationale for the amendment
The SAP has been amended to implement any changes to the planned analyses made during the 
course of the study since the approval of the previous version of the SAP and to incorporate any 
clarification to the text.
Modifications and changes
Global changes
The following global changes were applied to SAP version 1.0
!
Clarification that ‘Last Visit’ cannot use the baseline assessment
!
Specification that for ECGs, average of all interpretable readings at the visit will be used 
in summaries
!
Change in which questions contribute to which scale in the CBCL/6-18
!
Addition of Inhibitory self-control scale to BRIEF-P scoring table
!
Addition of question 28 to Pan/organize scale of BRIEF scoring table
!
Addition of Psychological Health Summary Score in pediatric quality of life inventory
!
LCM plasma concentrations are the only concentrations to be summarized. The 
presentation of specific dose levels has been added. Other AED concentrations are now 
only listed
!
Changes in the presentation of the Nonserious TEAEs
!
Presentation of compliance by visit has been removed
!
Addition of two new shift tables, one for single neurological parameters and one for 
physical examinations
!
Addition of summary of proportion of responders greater than 50 percent reduction in 
generalize seizures per 28 days during the study period by syndrome subgroup
!
Change of the name of phosphorus to phosphate, total serum protein to total protein and
blood urea nitrogen to urea nitrogen
!
Typographical corrections
!
Dating and version control
!
Addition of exploratory safety variables and its analyses
!
Addition of exploratory efficacy variables and its analyses
!
Change of some of the section numbers and name
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 43 of 53
Specific Changes
Change #1
Section 3.2.4 Last Visit
The Last Visit for all assessments in SP0966 is the last non-missing assessment during the 
Treatment Period. All scheduled and unscheduled assessments within this time period will be 
considered. Last Visit will be determined separately for each study procedure where Last Visit is 
mentioned within this document.
Has been changed to:
The Last Visit for all assessments in SP0966 is the last non-missing assessment during the 
Treatment Period. This cannot be the same assessment as the baseline assessment. All scheduled 
and unscheduled assessments within this time period will be considered. Last Visit will be 
determined separately for each study procedure where Last Visit is mentioned within this 
document.
Change #2
Section 8.5.2 Electrocardiograms
The average of all interpretable readings for a measurement will be used for summaries. 
Observed results and changes from Baseline in ECG results will be summarized for all visits and 
the Last Visit.
The number and percentage of subjects with no abnormality, an abnormal but not clinically 
significant finding, and a clinically significant finding, will be summarized by visit.
Has been changed to:
For ECGs, Baseline will be defined as the average of all pre-dose interpretable readings. For all 
post-Baseline visits, the average of all interpretable readings at the specified visit will be used for 
summaries. 
Observed results and changes from Baseline in ECG results will be summarized for all visits and 
the Last Visit.
The number and percentage of subjects with no abnormality, an abnormal but not clinically
significant finding, and a clinically significant finding, will be summarized by visit, including 
last visit.
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 44 of 53
Change #3
Table 8-2 CBCL/6-18
Syndrome scale
Questions
Aggressive behavior
3, 16, 19, 20, 21, 22, 23, 37, 57, 68, 86, 87, 88, 89, 94, 95, 97, 104
Anxious/depressed
14, 29, 30, 31, 32, 33, 35, 45, 50, 52, 71, 91, 112
Attention problems
1, 8, 10, 13, 17, 41, 61, 80
Rule-breaking behavior
26, 39, 43, 63, 67, 72, 73, 81, 82, 90, 96, 101, 106
Social problems
11, 12, 25, 27, 34, 36, 38, 48, 62, 64, 79
Somatic complaints
47, 49, 51, 54, 56a, 56b, 56c, 56d, 56e, 56, 56g
Thought problems
9, 18, 40, 46, 58, 59, 60, 66, 70, 76, 83, 84, 85, 92, 100
Withdrawn/depressed
42, 65, 69, 75, 102, 103, 111
Has been changed to:
Syndrome scale
Questions
Aggressive behavior
3, 16, 19, 20, 21, 22, 23, 37, 57, 68, 86, 87, 88, 89, 94, 95, 97, 104
Anxious/depressed
14, 29, 30, 31, 32, 33, 35, 45, 50, 52, 71, 91, 112
Attention problems
1, 4, 8, 10, 13, 17, 41, 61, 78, 80
Rule-breaking behavior
2, 26, 28, 39, 43, 63, 67, 72, 73, 81, 82, 90, 96, 99, 101, 105, 106
Social problems
11, 12, 25, 27, 34, 36, 38, 48, 62, 64, 79
Somatic complaints
47, 49, 51, 54, 56a, 56b, 56c, 56d, 56e, 56f, 56g
Thought problems
9, 18, 40, 46, 58, 59, 60, 66, 70, 76, 83, 84, 85, 92, 100
Withdrawn/depressed
5, 42, 65, 69, 75, 102, 103, 111
2, 33
2, 3
13, 17
3, 17
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28, 39
28, 39
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 45 of 53
Change #4
Table 8-3 BRIEF-P questionnaire scoring
Scale/Index
Questions
Inhibit
3, 8, 13, 18, 23, 28, 33, 38, 43, 48, 52, 54, 56, 58, 60, 62
Shift
5,10, 15, 20, 25, 30, 35, 40, 45, 50
Emotional Control
1, 6, 11, 16, 21, 26, 31, 36, 41, 46
BRI
All from {Inhibit, Shift, and Emotional Control}
Working Memory
2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 51, 53, 55, 57, 59, 61, 63
Plan/Organize
4, 9, 14, 19, 24, 29, 34, 39, 44, 49
MI
All from {Working Memory and Plan/Organize}
GEC Score
1-63
BRI=Behavioral Regulation Index, MI=Metacognition Index, GEC=Global Executive Composite
Has been changed to:
Scale/Index
Questions
Inhibit
3, 8, 13, 18, 23, 28, 33, 38, 43, 48, 52, 54, 56, 58, 60, 62
Shift
5,10, 15, 20, 25, 30, 35, 40, 45, 50
Emotional Control
1, 6, 11, 16, 21, 26, 31, 36, 41, 46
Inhibitory self-control
All from {Inhibit and Emotional Control}
Flexibility
All from {Shift, and Emotional Control}
Working Memory
2, 7, 12, 17, 22, 27, 32, 37, 42, 47, 51, 53, 55, 57, 59, 61, 63
Plan/Organize
4, 9, 14, 19, 24, 29, 34, 39, 44, 49
MI
All from {Working Memory and Plan/Organize}
GEC Score
1-63
MI=Metacognition Index, GEC=Global Executive Composite
REDACTED 
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 46 of 53
Change #5
Table 8-4 BRIEF questionnaire scoring
Scale/Index
Questions
BRI
All from {Inhibit, Shift, and Emotional Control}
Initiate
3, 10, 16, 47, 48, 61, 66, 71
Working Memory
2, 9, 17, 19, 24, 27, 32, 33, 37, 57
Plan/Organize
11, 15, 18, 22, 35, 36, 40, 46, 51, 53, 58
Organization of Materials
4, 29, 67, 68, 69, 72
Monitor
14, 21, 31, 34, 42, 52, 60, 63
MI
All from {Initiate, Working Memory, Plan/Organize, Organization 
of Materials, and Monitor}
GEC Score
1-72
BRI=Behavioral Regulation Index, MI=Metacognition Index, GEC=Global Executive Composite
Has been changed to:
Scale/Index
Questions
BRI
All from {Inhibit, Shift, and Emotional Control}
Initiate
3, 10, 16, 47, 48, 61, 66, 71
Working Memory
2, 9, 17, 19, 24, 27, 32, 33, 37, 57
Plan/Organize
11, 15, 18, 22, 28, 35, 36, 40, 46, 51, 53, 58
Organization of Materials
4, 29, 67, 68, 69, 72
Monitor
14, 21, 31, 34, 42, 52, 60, 63
MI
All from {Initiate, Working Memory, Plan/Organize, Organization 
of Materials, and Monitor}
GEC Score
1-72
MI=Metacognition Index, GEC=Global Executive Composite
REDACTED 
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 47 of 53
Change #6
Section 9.4 Pediatric Quality of Life Inventory
Each scale score is then calculated as the mean of the corresponding nonmissing items if 50% or 
more of the items are nonmissing. The same algorithm will be used to calculate an overall total 
scale score (all scales) for each subject.
Has been changed to:
Each scale score is then calculated as the mean of the corresponding nonmissing items if 50% or 
more of the items are nonmissing. The same algorithm will be used to calculate an overall Total 
Scale Score (all scales) and the Psychosocial Health Summary Score (a combination of the 
emotional, social and school functioning questions) for each subject.
Change #7
Section 10.1 Descriptive statistics of LCM and AED plasma concentrations 
The results of LCM and other AEDs plasma concentrations will be described by the method of 
descriptive statistics: n, >=limit of quantification (LOQ), arithmetic mean, SD, median, range, 
geometric mean, and geometric CV. Summary statistics will only be calculated if at least 2/3 of 
the data are above the lower LOQ. Values <LOQ will be set to LOQ/2 for the determination of 
summary statistics.
The summary of LCM and other AEDs plasma concentration will be presented by dose level 
during the Maintenance Period (dose with the longest duration during the Maintenance Period) 
and visit.
Has been changed to:
The results of LCM plasma concentrations will be described by the method of descriptive 
statistics: n, >=limit of quantification (LOQ), arithmetic mean, SD, median, geometric mean, and 
geometric CV. Summary statistics will only be calculated if at least 2/3 of the data are above the 
lower LOQ. Values <LOQ will be set to LOQ/2 for the determination of summary statistics.
The summary of LCM plasma concentrations will be presented by dose level during the 
Maintenance Period (dose with the longest duration during the Maintenance Period) and visit.
The dose levels will be combined as 4-6 mg/kg/day, 7-8 mg/kg/day, 9-10 mg/kg/day, and 11-12 
mg/kg/day.
Other AED plasma concentrations will only be listed.
Change #8
Section 8.2.2 Adverse Events 
The following summaries of AEs will be provided by primary SOC and PT:
!
TEAEs
!
TEAEs during the Titration Period
!
TEAEs during the Maintenance Period
!
TEAEs by syndrome subgroups (as described in Section 4.8)
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 48 of 53
!
TEAEs including subject numbers
!
Serious TEAEs
!
Serious TEAEs including subject numbers
!
TEAEs leading to discontinuation
!
TEAEs leading to discontinuation including subject numbers
!
TEAEs by maximum intensity
!
Nonserious TEAEs occurring in > 5% of subjects
!
Other significant TEAEs
Has been changed to:
The following summaries of AEs will be provided by primary SOC and PT:
!
TEAEs
!
TEAEs during the Titration Period
!
TEAEs during the Maintenance Period
!
TEAEs by syndrome subgroups (as described in Section 4.8)
!
TEAEs including subject numbers
!
Serious TEAEs
!
Serious TEAEs including subject numbers
!
TEAEs leading to discontinuation
!
TEAEs leading to discontinuation including subject numbers
!
TEAEs by maximum intensity
!
Nonserious TEAEs 
!
Nonserious TEAEs occurring in > 5% of subjects
!
Other significant TEAEs
Change #9
Section 8.2.2 Adverse Events 
The following summaries by primary SOC and PT will be presented overall only (ie, not by age 
group).
!
Nonserious TEAEs 
!
TEAEs by relationship to LCM
!
Serious TEAEs by relationship to LCM
!
Nonserious TEAEs by relationship to LCM
REDACTED 
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 49 of 53
!
Fatal TEAEs by relationship to LCM
!
Nonserious TEAEs occurring in at least 5% of subjects by relationship
Has been changed to:
The following summaries by primary SOC and PT will be presented overall only (ie, not by age 
group).
!
TEAEs by relationship to LCM
!
Serious TEAEs by relationship to LCM
!
Nonserious TEAEs by relationship to LCM
!
Fatal TEAEs by relationship to LCM
!
Nonserious TEAEs occurring in at least 5% of subjects by relationship
Change #10
Section 7.2 Presentation of compliance
Compliance will be summarized separately for the Treatment Period, the Titration Period, the 
Maintenance Period and each visit for the SS.  It will be presented with descriptive statistics and 
additionally categorized as <75%, ≥75% to ≤125%, and >125% 
Has been changed to:
Compliance will be summarized separately for the Treatment Period, the Titration Period and the 
Maintenance Period. It will be presented with descriptive statistics and additionally categorized 
as <75%, ≥75% to ≤125%, and >125% 
Change #11
Section 8.5.3 Physical and Neurological Examinations
Summaries of shift from Baseline to Visit 9/ET will be provided based on categories normal, 
abnormal, not clinically significant, and abnormal, clinically significant for each of the single 
neurological examinations. Examinations at other visits will only be listed. 
Has been changed to:
Summaries of shift from Baseline to Visit 9/ET will be provided based on categories normal, 
abnormal, not clinically significant, and abnormal, clinically significant for each of the single 
neurological examinations. Summaries of shift from Baseline normal to any post-baseline 
abnormal, clinically significant category for each of the neurological examinations will also be 
provided. For physical examination summaries of shift from Baseline normal to any post-
baseline abnormal, clinically significant category will be presented. 
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 50 of 53
Change #12
Section 2.2.1.4 Exploratory safety variables 
Has been added:
Decrease in generalized spike-wave discharges on 24-hour ambulatory EEG by syndrome 
subgroups.
Change #13 
Section 8.4 Clinical laboratory evaluations
Chemistry: calcium, serum electrolytes (sodium, potassium, chloride, bicarbonate), total serum 
protein, albumin, phosphorus, glucose, uric acid, alkaline phosphatase, blood urea nitrogen, 
creatinine, aspartate aminotransferase, alanine aminotransferase, gamma glutamyltransferase, 
total bilirubin, cholesterol, triglycerides
Has been changed to:
Chemistry: calcium, serum electrolytes (sodium, potassium, chloride, bicarbonate), total protein, 
albumin, phosphate, glucose, uric acid, alkaline phosphatase, urea nitrogen, creatinine, aspartate 
aminotransferase, alanine aminotransferase, gamma glutamyltransferase, total bilirubin, 
cholesterol, triglycerides
Change #14
Section 8.3 Exploratory safety variables 
Has been added as a new section
A frequency table will be presented for the number of subjects with a decrease of at least 30% 
and a decrease of at least 50% in generalized spike-wave discharges on 24-hour EEG at Visit 6 
compared to Baseline by syndrome subgroups
Change #15
Section 2.2.2 Preliminary efficacy variables 
Has been changed to:
Section 2.2.2 Efficacy variables 
Change #16
Section 2.2.2 Preliminary efficacy variables 
Has been changed to:
Section 2.2.2.1 Preliminary efficacy variables 
Change #17
New section 2.2.2.2 exploratory efficacy variables has been added 
Change #18
Section 9 Analyses of Preliminary Efficacy Variables
Has been changed to:
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 51 of 53
Section 9 Analyses of Efficacy Variables
Change #19
Section 9.1 Seizure days
Has been changed to:
Section 9.1 Preliminary Efficacy Variables
Change #20
Section 9.1 Seizure days
Has been changed to:
Section 9.1.1 Seizure days
Change #21
Section 9.2 Clinical Global Impression of Change
Has been changed to:
Section 9.1.2 Clinical global impression of change
Change #22
Section 9.3 Caregivers Global Impression of Change
Has been changed to:
Section 9.1.3 Caregivers global Impression of change
Change #23
Section 9.4 Pediatric Quality of Life Inventory
Has been changed to:
Section 9.1.4 Pediatric quality of life inventory
Change #24
Section 9.5 Health care resource use
Has been changed to:
Section 9.1.5 Health care resource use
Change #25
New section 9.2 Exploratory Efficacy Variables
Has been added:
The analysis of the exploratory efficacy variable will be conducted for the FAS.
Days with seizures per 28 days for each seizure type and study period will be calculated as 
described for the generalized seizures in Section 8.1.2. The days with any generalized seizures 
per 28 days will only be derived for subjects who completed or discontinued during the 
REDACTED 
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UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 52 of 53
respective study period. For subjects who discontinued during the Titration period, the missing 
value of the maintenance period will be implemented as described in Section 4.2
Descriptive statistics will be used to summarize the proportion of subjects who have at least a 50 
percent reduction in generalized seizures per 28 days by study period (Titration and Maintenance 
Period) and syndrome subgroup.
Descriptive statistics will also be produced to summarize the proportion of subjects who have 
more than 30% and 50% increase in generalized seizures per 28 days during the study period 
(Titration and Maintenance Period) by syndrome.
REDACTED COPY 
This document cannot be used to support any marketing authorization application and any extensions or variations 
d 
thereof. 


UCB
06 March 2018
Statistical Analysis Plan
Lacosamide
SP0966
Confidential
Page 53 of 53
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE
This document has been reviewed and approved per the Review and Approval of Clinical 
Documents Standard Operating Procedures. Signatures indicate that the final version of the 
Statistical Analysis Plan (SAP) or amended SAP is released for execution.
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This document cannot be used to support any marketing authorization application and any extensions or variations thereof. 


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