Conditions: Epilepsy With Partial On-set Seizures
Keywords: epilepsy seizures partial on-set seizures
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 102
Healthy volunteers: no

Brief summary:
A study of a drug to be used in addition with another drug to treat adults with Uncontrolled Partial-onset Seizures

Detailed description:
This is a 31-week, multicenter, 2-arm, prospective, open-label, non-randomized, Phase 4 study of eslicarbazepine acetate (ESL) as adjunctive therapy in adult subjects with a diagnosis of epilepsy with POS. Two groups of ESL-naïve subjects will be evaluated. The groups are defined as follows:

* Arm 1 (ESL as first add-on): This group will include subjects who have been maintained on a regimen consisting of a stable dose of LEV or LTG for at least 1 month (28 days) prior to screening and who have not used any adjunctive treatment.
* Arm 2 (ESL as later add-on): This group will include subjects who have been maintained on a regimen consisting of a stable dose of 1-2 AEDs (excluding oxcarbazepine \[OXC\]) for at least 1 month (28 days) prior to screening and who have used adjunctive treatment in the past.

The Arm 1 subjects will allow an assessment of the efficacy and safety of ESL in subjects who are early in the course of their disease and being treated with one of the most common first line AEDs.

The subjects in Arm 2 are similar to the subject population in the ESL Phase 3 adjunctive epilepsy studies, treatment-resistant subjects who are later in the course of their disease. The inclusion of these subjects in the present study will provide an assessment of the efficacy and safety of ESL as a later adjunctive therapy in a real world clinical setting.

In addition, this study will provide data from both Arm 1 and Arm 2 for several behavioral, mood-related, and QOL-related assessments that were not evaluated in the ESL Phase 3 adjunctive epilepsy program.

The study will consist of a Screening Phase of 1 to 2 weeks, followed by a 2-week Titration Phase, a 24-week Maintenance Phase, and a Safety Follow-up/Taper Phase of 4 weeks. The last visit in the Maintenance Phase (Visit 9) is considered the End of Study (EOS) visit

Arms:
arm 1: eslicarbazepine acetate (as first add-on)mg/day as medically indicated at the discretion of Investigator up to a maximum dose of 1200 mg/day (Canadian sites) or 1600 mg/day (US sites) arm 2: eslicarbazepine acetate (as later add-on)

Interventions: intervention 1: Eslicarbazepine acetate intervention 2: Eslicarbazepine Acetate
Intervention descriptions: intervention 1: eslicarbazepine acetate tablets, taken once daily. Subjects begin 2-week Titration Phase starting on Day 1 (Week 1), by initiating treatment with ESL 400 mg/day. Subjects titrate to minimum dose of 800 mg/day for the 24-week Maintenance Phase beginning at Week 3. In the Maintenance Phase, subjects may titrate in weekly increments of 400 mg/day as medically indicated at the discretion of Investigator up to a maximum dose of 1200 mg/day (Canadian sites) or 1600 mg/day (US sites) intervention 2: eslicarbazepine acetate acetate tablets, taken once daily. Subjects begin 2-week Titration Phase starting on Day 1 (Week 1), by initiating treatment with ESL 400 mg/day. Subjects titrate to minimum dose of 800 mg/day for the 24-week Maintenance Phase beginning at Week 3. In the Maintenance Phase, subjects may titrate in weekly increments of 400 mg/day as medically indicated at the discretion of Investigator up to a maximum dose of 1200 mg/day (Canadian sites) or 1600 mg/day (US sites)

Protocol document:
Prot_000.pdf: 
Titlpage
 
 
 
Eslicarbazepine Acetate 
Clinical Study Protocol SEP093-701 
 
Efficacy and Safety of Eslicarbazepine Acetate as First Add-on to 
Levetiracetam or Lamotrigine Monotherapy or as Later 
Adjunctive Treatment for Subjects with Uncontrolled 
Partial-onset Seizures: A Multicenter, Open-label, 
Non-randomized Trial 
 
IND No. 67,466 
 
 
Version 3.01 
16 November 2017 
Incorporating Non-substantial Amendment 1.00 
 
 
 
SUNOVION PHARMACEUTICALS INC. 
84 Waterford Drive 
Marlborough, MA 01752, USA 
(508) 481-6700 


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RESTRICTED DISTRIBUTION OF PROTOCOLS 
This protocol and the data gathered during the conduct of this protocol contains information that 
is confidential and/or of proprietary interest to Sumitomo Dainippon Pharma Co. Ltd. and/or 
Sunovion Pharmaceuticals Inc. (including their predecessors, subsidiaries or affiliates). The 
information cannot be disclosed to any third party or used for any purpose other than the purpose 
for which it is being submitted without the prior written consent of the appropriate Sumitomo 
Dainippon Pharma Company. 
This information is being provided to you for the purpose of conducting a study for Sunovion 
Pharmaceuticals, Inc. You may disclose the contents of this protocol to the study personnel under 
your supervision and to your Institutional Review Board or Independent Ethics Committee for 
the above purpose. You may not disclose the contents of this protocol to any other parties, unless 
such disclosure is required by government regulations or laws, without the prior written 
permission of Sunovion Pharmaceuticals Inc. 
Any supplemental information (eg, a protocol amendment) that may be added to this document is 
also proprietary to Sunovion Pharmaceuticals Inc., and should be handled consistently with that 
stated above. 


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EMERGENCY CONTACTS 
Table 1: Emergency Contact Information 
Role in Study 
Name 
Contact Information 
Responsible Physician 
 
 
Medical Monitor  
 
 
SAE/Pregnancy Reporting  
 
  


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1. 
SYNOPSIS 
Name of Sponsor: Sunovion Pharmaceuticals Inc. 
Name of Investigational Product: Aptiom® 
Name of Active Ingredient: Eslicarbazepine acetate (ESL) 
Title of Study: Efficacy and Safety of Eslicarbazepine Acetate as First Add-on to Levetiracetam or 
Lamotrigine Monotherapy or as Later Adjunctive Treatment for Subjects with Uncontrolled 
Partial-onset Seizures: A Multicenter, Open-label, Non-randomized Trial 
Proposed Indication: Adjunctive treatment for subjects with partial-onset seizures (POS) 
Study Centers: Multicenter with sites in the United States and Canada 
Phase of Development: 4 
Study Objectives:  
Primary Objective: To evaluate the effectiveness (measured by study retention rate) of ESL 
administered once daily (QD) as the first adjunctive therapy to levetiracetam (LEV) or lamotrigine 
(LTG) or as later adjunctive therapy in subjects with POS over a 24-week maintenance period in a 
real-world clinical setting.  
Secondary Objectives:  
 
To evaluate the efficacy of ESL QD as a first or later adjunctive therapy based on the 
number of seizures reported via a standardized paper daily diary over a 24-week 
maintenance period. 
 
To evaluate the safety and tolerability of ESL QD as a first or later adjunctive therapy. 
 
To evaluate the effect of treatment with ESL QD on the quality of life (QOL), behavior, 
and mood. 
Exploratory Objectives:  
 
To evaluate the accuracy of an investigational wearable watch device from Empatica in 
recording seizure counts.  
 
To evaluate the performance of an investigational electronic seizure diary in the form of a 
smartphone application (Empatica MATE). 
Study Design:  
This is a 31-week, multicenter, 2-arm, prospective, open-label, non-randomized, Phase 4 study of ESL 
as adjunctive therapy in adult subjects with a diagnosis of epilepsy with POS. Two groups of 
ESL-naïve subjects will be evaluated. The groups are defined as follows: 
 
Arm 1 (ESL as first add-on): This group will include subjects who have been maintained 
on a regimen consisting of a stable dose of LEV or LTG for at least 1 month (28 days) 
prior to screening and who have not used any adjunctive treatment.  
 
Arm 2 (ESL as later add-on): This group will include subjects who have been maintained 
on a regimen consisting of a stable dose of 1 - 2 anti-epileptic drugs (AEDs) (excluding 
oxcarbazepine [OXC]) for at least 1 month (28 days) prior to screening and who have used 
adjunctive treatment in the past. 


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The Arm 1 subjects will allow an assessment of the efficacy and safety of ESL in subjects who are 
early in the course of their disease and being treated with one of the most common first line AEDs. The 
subjects in Arm 2 are similar to the subject population in the Phase 3 adjunctive studies, treatment-
resistant subjects who are later in the course of their disease. The inclusion of these subjects in the 
present study will provide an assessment of the efficacy and safety of ESL as a later adjunctive therapy 
in a real world clinical setting. In addition, this study will provide data from both Arm 1 and Arm 2 for 
several behavioral, mood-related, and QOL-related assessments that were not evaluated in in the 
Phase 3 program. 
Approximately 190 subjects will be enrolled (approximately 93 subjects in Arm 1 and 97 subjects in 
Arm 2). 
The study will consist of a Screening Phase of 1 to 2 weeks, followed by a 2-week Titration Phase, a 
24-week Maintenance Phase, and a Safety Follow-up/Taper Phase of 4 weeks. The last visit in the 
Maintenance Phase (Visit 9) is considered the End of Study (EOS) visit. 
The screening visit should take place 7 - 10 days prior to the titration visit, and may be extended to 
7 - 17 days if required with consent of medical monitor. Subjects of Asian ancestry who require 
HLA-B*1502 testing (eg do not have prior test results) may have the screening visit 7 - 17 days prior to 
the titration visit. 
Subjects who withdraw prior to the EOS visit should have an Early Discontinuation Visit (EDV) within 
72 hours.  
During the study, there will be 9 site visits and 2 scheduled telephone visits. The follow-up contact to 
collect information on AEs and concomitant medications may occur at a site visit or by a telephone 
call. 
The procedures and assessments performed in this study are described in Table 2. 
The study population has been selected to be similar to subjects treated in a clinical setting. The study 
will include subjects ≥ 18 years old who meet the study inclusion, do not meet exclusion criteria and 
who can provide written informed consent. In order to be eligible for participation in the study, subjects 
of Asian ancestry (or subjects for whom the absence of Asian ancestry cannot be confirmed) must sign 
an additional genetic consent to undergo blood testing for the human leukocyte antigen (HLA)-B*1502 
allele unless they can provide documentation of prior testing to confirm non-carrier status. Asian 
ancestry will be based on subject self-report. 
Signed informed consent, (including genetic consent for subjects of Asian ancestry, or subjects for 
whom the absence of Asian ancestry cannot be confirmed) will be obtained prior to performing any 
study procedures. 
Subjects will complete the pre-Human Epilepsy Project (HEP) instrument at screening. The HEP 
instrument is a form administered by an Investigator to obtain a retrospective seizure history, in as 
accurate a manner as possible, in the absence of a retrospective seizure diary. The caregiver may 
contribute to the HEP data. These data will be used for seizure history only. As part of completing the 
HEP instrument, the Diagnostic Interview for Seizure Classification Outside of Video EEG Recording 
(DISCOVER) will be administered. The DISCOVER form allows researchers to ask subjects with 
epilepsy questions about the subject’s seizures in order to increase the likelihood of proper diagnosis 
and to standardize seizure classification. The intent is to ensure that the subject will use correct and 
consistent terminology to describe seizure history and when they complete their daily seizure diaries 
throughout the study. The information on the seizures recorded on the DISCOVER form will not be 
utilized for seizure analyses; it will be used for diagnostic and coding purposes only. 
Seizure history at screening will be derived from the HEP. The subject will be asked about the number 
and types of seizures that occurred for the longest available period up to 3 months prior to screening. 
These data will be recorded by the Investigator on a separate seizure history case report form. 
During the study, the number of seizures by type will be obtained from subject entries in a standard


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paper seizure diary and electronic seizure diary daily starting at Visit 1 and up to Visit 9 (EOS, the end 
of the 24-week Maintenance Phase). The diaries require an entry every day whether a seizure occurs or 
not. Subjects will record information for each seizure by date and type of seizure.  
The subject will also be issued an investigational wearable seizure detection device at Visit 1 to collect 
exploratory data evaluating the identification of seizure activity based on skin conduction. The subject 
will wear the watch throughout the duration of the study, up to Visit 9. 
Eligible subjects will begin the 2-week Titration Phase on Day 1 (Week 1), during which they will 
initiate treatment with ESL 400 mg/day and remain on that dose for 1 week (Days 1 – 7). Subjects will 
titrate to ESL 800 mg/day the beginning of week 2 (Day 8) and will remain on that dose for 1 week up 
to the beginning of the maintenance phase. Subjects will maintain a minimum dose of 800 mg/day for 
the Maintenance Phase; however, during the Maintenance Phase, subjects may titrate in weekly 
increments of 400 mg/day as medically indicated at the discretion of the Investigator up to a maximum 
dose of 1200 mg/day (Canadian sites) or 1600 mg/day (United States [US] sites), (based on maximum 
local labelled dose). Additional details are provided in Section 10.1.1. 
Subjects who complete the 24-week Maintenance Phase may choose to continue treatment with 
commercial ESL. Subjects who chose not to continue treatment with ESL at the end of the 
Maintenance Phase will be gradually tapered off drug provided that they do not have an AE that 
requires abrupt discontinuation of the study drug. 
Subjects who prematurely discontinue treatment with ESL for any reason will be gradually tapered off 
study drug unless abrupt discontinuation of the drug is required for the treatment of an AE. Subjects 
who prematurely discontinue treatment with ESL will be withdrawn from the study. 
Subjects should maintain their concomitant AED(s) at a constant dosage during the Titration Phase and 
Maintenance Phase of the study. However, subjects on concomitant carbamazepine (CBZ) may have a 
dose reduction (up to 25% of the total daily dose taken at study entry) in the last week of the titration 
period (Week 2) or the first week of the Maintenance Phase (Week 3), if the subject has intolerable 
AEs related to an association between CBZ and ESL in the opinion of the Investigator. This reduction 
must be approved by the Medical Monitor. In addition, subjects taking phenytoin who experience 
intolerable AEs suggestive of phenytoin toxicity may have their dose of phenytoin reduced up to 15%, 
with the approval of the Medical Monitor. For patients who become seizure free during the trial, 
patients may reduce dose of baseline AEDs by a maximum of 25% to improve overall tolerability at the 
discretion of the Investigator. After the end of the Maintenance Phase, AEDs may be adjusted at the 
discretion of the Investigator. 
Subjects who are tolerant of ESL who have not had a rash or allergic reaction for at least 6 weeks and 
who provide a separate optional written genetic consent will be asked for a saliva sample for HLA 
genotyping. They will also be asked to complete a questionnaire relating to rash risk factors at or after 
Visit 4. Information from subjects who participate will be used as the control group in a separate rash 
registry study of risk associated with HLA type. 
Subjects who report a serious adverse event (SAE) of rash or other allergic reaction regardless of 
causality at any time during the study will be asked to provide consent to be contacted by the 
University of Pennsylvania on behalf of Sunovion for participation in the separate rash registry study. 
Number of Subjects (planned): Approximately 190 subjects will be enrolled as available to either 
Arm 1 or Arm 2 as defined above. 
Diagnosis and Main Criteria for Subject Inclusion:  
Following are the main inclusion and exclusion criteria, complete lists of all inclusion and exclusion 
criteria for this study are provided in Section 8. 
Main Inclusion Criteria 
 
Male or female subjects ≥ 18 years of age. 


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 
Subject is willing and able to sign informed consent. 
 
Subject has a documented diagnosis of epilepsy with simple POS with a motor component 
or complex POS with or without secondarily generalized seizures as defined in the 
Classification of Seizures of the International League Against Epilepsy (ILAE, 1981). 
 
Subject has a documented electroencephalogram within 10 years prior to screening.  
 
Subject has had at least 3 POS during previous six months. 
 
Subject has had a sufficient number of seizures at time of enrollment to justify adjunctive 
therapy, as determined by the Investigator. 
 
Subjects are required to be ESL-naïve AND  
 
Maintained on a stable LEV or LTG regimen for at least 1 month (28 days) prior to 
screening with no history of adjunctive treatment (for Arm 1, ESL as first add-on). 
OR 
 
Maintained on a stable dose of 1 - 2 AEDs (excluding OXC) for at least 1 month 
(28 days) prior to screening and who have had prior adjunctive treatment (for Arm 2, 
ESL as later add-on). 
 
Except for epilepsy, subject is judged to be in general good health based on medical 
history, physical examination findings, and clinical laboratory test results. 
Main Exclusion Criteria 
 
Subjects with a prior exposure to ESL. 
 
Subjects currently being treated with OXC. 
 
Subject with a history of allergic reaction to OXC or CBZ, or a history of serious allergic 
reaction (Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic 
Symptoms or similar) to any AED, or a history of serious allergic reactions to other 
medications. 
 
Subject has a history of status epilepticus or cluster seizures (ie, 3 or more seizures within 
30 minutes) within the 3 months prior to screening. 
 
Subject has had seizures of psychogenic origin or purely subjective seizures within the last 
2 years. 
 
Subject has a known progressive structural central nervous system (CNS) lesion, 
progressive encephalopathy, or a progressive cerebral abnormality. 
 
Subject whose current seizures are related to an acute medical illness or other non-epileptic 
origin. 
 
Subjects who are not able to complete the diaries in the Investigator’s opinion. 
 
Subject is pregnant, currently nursing, or intends to become pregnant during the study 
period or within 30 days of the last dose of study drug. 
 
Subjects of Asian ancestry will be excluded if they are carriers of HLA-B*1502. Either: 
 
Subject must give written informed consent for genotyping, and test negative. 
OR  
 Subjects must provide documentation of prior testing confirming non-carrier status. 


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Study Drug (Aptiom), Dosage and Mode of Administration:  
The drug dosage form will be commercial tablets of 400 mg Aptiom (ESL) in 30 count bottles with an 
added supplemental study label. An Interactive Web/Voice Response System will be used to manage 
subject screening and enrollment. 
Tablets will be taken by mouth, QD. 
Aptiom may be taken with or without food. Tablets may be crushed and mixed with food if the subject 
is incapable of swallowing a tablet. All tablets must be taken simultaneously. Subjects are to take study 
drug at approximately the same time each day. 
Duration of Treatment: 30 weeks 
Reference Therapy, Dosage and Mode of Administration: None 
Concomitant Medications: 
The following medications are prohibited during the study. Subject may not have taken any medication 
prohibited for this protocol within 4 weeks prior to screening. 
 
OXC. 
 
Warfarin, felbamate, vigabatrin, and perampanel (unless at stable dose with safety testing 
for ≥1 year). 
 
Ezogabine. 
 
Other experimental/investigational drugs taken as part of a clinical trial. 
The following drugs and treatments are allowed during the study: 
 
Vagus nerve stimulation. 
 
Steroids. 
 
Benzodiazepines at stable dose (as AEDs).  
 
Chronic medications (other than those prohibited, taken at a stable dose). 
 
Any other drug that, in the opinion of the Investigator is necessary for the medical 
treatment of the subject, provided it is not a prohibited medication. 
See Section 10.2 to Section 10.4 of the full protocol for further discussion of concomitant medications.  
Study Endpoints:  
Primary Endpoint: The proportion of subjects completing 24 weeks adjunctive therapy during 
Maintenance Phase (Visit 9).  
Efficacy Endpoints: 
 
Seizure data via the paper diary will be used to calculate the following seizure related 
endpoints: 
 
Standard Seizure Frequency (SSF) during the first 12 weeks, the last 12 weeks, and the 
24 weeks of the Maintenance Phase.  
 
50% and 75% responder rate (calculated as 50% and 75% reduction in SSF from 
baseline) as evaluated during the first 12 weeks, the last 12 weeks, and the 24 weeks of 
the Maintenance Phase. 
 
Relative reduction (%) in SSF from baseline during the first 12 weeks, the last 
12 weeks, and the 24 weeks of the Maintenance Phase. 
 
Proportion of seizure-free subjects during the first 12 weeks, the last 12 weeks, and the 


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24 weeks of the Maintenance Phase. 
 
Time on ESL. 
Other Endpoints:  
 
Changes from baseline in the Neurological Disorders Depression Inventory for Epilepsy 
(NDDI-E)-6-item questionnaire. 
 
Changes from baseline in the Profile of Mood States Short-form (POMS-SF). 
 
Changes from baseline in the agitation/behavioral measurements as evaluated by the 
Modified Overt Aggression Scale (MOAS). 
 
Changes from baseline in Quality of Life in Epilepsy-Patient-Weighted (QOLIE-31-P) 
scores. 
 
Changes from baseline in EuroQol Five Dimensions Questionnaire (EQ-5D) scores. 
 
Clinical Global Impression of Improvement (CGI-I) scores at each evaluation time point. 
 
Patient’s Global Impression of Change (PGI-C) scores at each evaluation time point. 
Safety Endpoints:  
 
Number and percentage of subjects with AEs. 
 
Number and percentage of subjects with SAEs. 
 
Number and percentage of subjects with AEs leading to discontinuation. 
 
Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS): Proportion (%) of events 
in each classification class (as completed by the subject). 
 
Changes from baseline in clinical laboratory parameters including thyroid panel. 
 
Changes from baseline in vital signs parameters. 
 
Score of AED-specific AEs (by the Liverpool Adverse Event Profile [LAEP]). 
Exploratory Endpoints: 
 
Seizure data recorded by an investigational wearable watch device from Empatica.  
 
Seizure data recorded by an investigational electronic seizure diary from Empatica MATE 
application. 
Statistical Methods: The Statistical Analysis Plan will provide details on the statistical methods 
planned for this study and will be finalized prior to the database lock. All endpoints will be 
summarized descriptively for Arm 1 and Arm 2 separately. There will be no statistical comparisons 
between Arm 1 and Arm 2. 
The proportion of subjects completing 24 weeks of the Maintenance Phase and the 95% confidence 
interval (CI) will be calculated. SSF, 50% and 75% responder rates, relative reduction in SSF, and 
proportion of seizure-free subjects during the first 12 weeks, the last 12 weeks, and the 24 weeks of the 
Maintenance Phase will be calculated separately. Time on ESL will be calculated from the first dose to 
the last known dose of ESL. 
All AEs will be summarized by calculating the number and percent of subjects with AEs, system organ 
class and preferred term. Deaths, serious AEs, and AEs leading to study discontinuation will be 
summarized. 
Clinical laboratory and vital signs variables will be summarized by calculating summary statistics on 
the actual values and on the change from baseline. Shift tables from baseline to the end of this study 


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will be provided for laboratory parameters.  
For eC-SSRS score, the percentage of subjects in each classification class for overall and at each 
assessment time will be summarized. 
NDDI-E, POMS-SF, MOAS, QOLIE-31-P, and EQ-5D scores will be summarized for each evaluation 
time point; changes from baseline will also be summarized. CGI-I and PGI-C scores will be 
summarized for each evaluation time point. 
Sample Size:  
Arm 1 (first add-on): Assuming a completion rate of 60% at 24 weeks of the Maintenance Phase for 
Arm 1, to show the lower limit of the 95% CI in the rate to be 50% (50%, 70%), the sample size is 
estimated at approximately 93 subjects.  
Arm 2 (later add-on): Assuming the completion rate of 50% at 24 weeks of the Maintenance Phase for 
Arm 2, to show the lower limit of the 95% CI in the rate to be 40% (40%, 60%), the sample size is 
estimated at approximately 97 subjects. 
Total estimates subjects enrollment is approximately 190 subjects. 
Sample size is calculated based on the precision (a half width of the 95% CI) for the estimate of the 
completion rate as assumed as above and is used the Normal approximation to the Binomial 
distribution. 
 


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Table 2: Schedule of Assessments 
Study Period 
Screening 
Titrationa 
24-Week Maintenance Phasea  
EDVa 
Safety Follow-up 
Visit 
V1 
V2 
V3 
V4 
TC1 
V5 
V6 
TC2 
V7 
V8 
V9  
(EOS) 
V10 or TC3 
Week 
-1 to -2o 
WKs 
WK 1 
Day 1 
WK
3 
WK
7 
WK
9 
WK
11 
WK
15 
WK 
17 
WK
19 
WK
23 
WK 
27 
- 
WK 
31 
Windows (days) 
(+3)o 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
±7 
Procedures 
 
Informed Consent 
Form 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Genetic Consent for 
HLA-B*1502 
Characterization: 
Subjects of Asian 
Ancestry onlyb,o 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Genetic Consent for 
HLA genotyping 
(optional)c 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Review of Inclusion/ 
Exclusion Criteria 
X 
X 
- 
- 
- 
- 
- 
- 
- 
- 
 
- 
- 
Demographics 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Medical and 
Neurologic History 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Complete 
DISCOVER form 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Administer HEP and 
Collect Seizure 
History Datad 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Prior/Concomitant 
Medicationse 
X 
X 
X 
X 
- 
X 
X 
- 
X 
X 
X 
X 
X 
Physical/Neurologic 
Examination 
X 
- 
X 
X 
- 
X 
X 
- 
- 
X 
X 
X 
- 
Vital Signs 
X 
X 
X 
X 
- 
X 
X 
- 
X 
X 
X 
X 
- 
Body Weight 
X 
X 
X 
X 
- 
X 
X 
- 
X 
X 
X 
X 
- 
Height 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 


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Table 2: 
Schedule of Assessments (Continued) 
Study Period 
Screening 
Titrationa 
24-Week Maintenance Phasea  
EDVa 
Safety Follow-up 
Visit 
V1 
V2 
V3 
V4 
TC1 
V5 
V6 
TC2 
V7 
V8 
V9  
(EOS) 
V10 or TC3 
Week 
-1 to -2o 
WKs 
WK 1 
Day 1 
WK
3 
WK
7 
WK
9 
WK
11 
WK
15 
WK 
17 
WK
19 
WK
23 
WK 
27 
- 
WK 
31 
Windows (days) 
+3 o 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
±7 
Procedures 
 
12-lead ECG 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
-
Clinical Laboratory 
Testsf 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
- 
Thyroid panel (free 
T3, T4, and TSH) 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
- 
Blood Sample for 
HLA-B*1502 testing: 
Subjects of Asian 
ancestry onlyg 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Genetic Saliva 
Sample and 
Questionnaire 
(optional)h 
- 
- 
- 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Serum β-hCGi 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
- 
Urine Pregnancy Testi 
- 
X 
X 
X 
- 
X 
X 
- 
X 
X 
 
 
Urine Drug Screen 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Liverpool Adverse 
Event Profilej  
- 
X 
X 
X 
- 
X 
X 
- 
X 
X 
X 
X 
- 
Adverse Events 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pre-treatment Adverse 
Events 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Dispense Study Drug 
- 
X 
X 
X 
- 
X 
X 
- 
X 
X 
Xk 
Xp 
- 
Collect Study Drug 
- 
- 
X 
X 
- 
X 
X 
- 
X 
X 
X 
X 
- 


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Table 2: 
Schedule of Assessments (Continued) 
Study Period 
Screening 
Titrationa 
24-Week Maintenance Phasea  
EDVa 
Safety Follow-up 
Visit 
V1 
V2 
V3 
V4 
TC1 
V5 
V6 
TC2 
V7 
V8 
V9  
(EOS) 
V10 or TC3 
Week 
-1 to -2o 
WKs 
WK 1 
Day 1 
WK
3 
WK
7 
WK
9 
WK
11 
WK
15 
WK 
17 
WK
19 
WK
23 
WK 
27 
- 
WK 
31 
Windows (days) 
+3 o 
- 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
±3 
- 
±7 
Procedures 
 
Record Any ESL 
Dose Change Since 
Last Visit 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
- 
Record Any AED 
Dose Change Since 
Last Visit 
- 
- 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
- 
Distribute Empatica 
Watchl 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Distribute Electronic 
Seizure Diarym 
X 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
Distribute Paper 
Seizure Diarym 
X 
X 
X 
X 
- 
X 
X 
- 
X 
X 
X 
X 
- 
Collect Paper Seizure 
Diary 
- 
X 
X 
X 
- 
X 
X 
- 
X 
X 
X 
X 
- 
Review Seizure 
Diaries 
 
X 
X 
X 
- 
X 
X 
- 
X 
X 
X 
X 
Xq 
EQ-5D 
- 
X 
- 
- 
- 
X 
- 
- 
- 
- 
X 
X 
- 
CGI-I 
- 
X 
- 
- 
X 
- 
- 
- 
- 
X 
X 
- 
PGI-C  
- 
X 
- 
- 
X 
- 
- 
- 
- 
X 
X 
- 
QOLIE-31-P 
- 
X 
- 
- 
- 
X 
- 
- 
- 
- 
X 
X 
- 
POMS-SF 
- 
X 
- 
- 
- 
X 
- 
- 
- 
- 
X 
X 
- 
NDDI-E 
- 
X 
- 
- 
- 
X 
- 
- 
- 
- 
X 
X 
- 
MOAS 
- 
X 
- 
- 
- 
X 
- 
- 
- 
- 
X 
X 
- 
eC-SSRSn 
X 
X 
X 
X 
- 
X 
X 
- 
X 
X 
X 
X 
- 
Return of watch and 
data collection device 
- 
- 
- 
- 
- 
- 
- 
- 
- 
- 
X 
X 
- 


Protocol SEP093-701, Version 3.01 
 
Eslicarbazepine acetate 
Confidential and Proprietary 
 
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16 November 2017 
Abbreviations: AED = Antiepileptic drug; β-hCG = Beta-human chorionic gonadotropin; CGI-I – Clinical Global Impression of Improvement; CRF = case report form; 
eC-SSRS = electronic Columbia-Suicide Severity Rating Scale; DISCOVER = Diagnostic Interview for Seizure Classification Outside of Video EEG Recording; 
ECG = Electrocardiogram; EDV = Early Discontinuation Visit; EOS = End of Study; EQ-5D = EuroQol Five Dimensions Questionnaire; ESL = Eslicarbazepine acetate; 
HEP = pre-Human Epilepsy Project; HLA = Human Leukocyte Antigen; MOAS = Modified Overt Aggression Scale; NDDI-E = Neurological Disorders Depression Inventory for 
Epilepsy; PGI-C = Patient’s Global Impression of Change; POMS-SF = Profile of Mood States Short-form; QOLIE-31-P = Quality of Life in Epilepsy-Patient-Weighted 
(31-item); T3 = Triiodothyronine; T4 = Thyroxine; TC = telephone call; TSH = Thyroid Stimulating Hormone; US = United States; WK = Week 
a  Eligible subjects will begin the 2-week Titration Phase on Day 1 (Week 1), during which they will initiate treatment with ESL at 400 mg/day and remain on that dose for 1 week 
(Days 1 – 7). Subjects will titrate to ESL 800 mg/day the beginning of week 2 (Day 8) and will remain on that dose for 1 week up to the beginning of the maintenance phase. 
Subjects will maintain a minimum dose of 800 mg/day for the Maintenance Phase; however, during the Maintenance Phase, subjects may titrate in weekly increments of 
400 mg/day as medically indicated at the discretion of the Investigator up to a maximum dose of 1200 mg/day (Canadian Sites) or 1600 mg/day (US sites), (based on maximum 
local labelled dose). Additional details are provided in Section 10.1.1. Subjects who withdraw prior to the (end of study) EOS visit should have an early discontinuation visit 
(EDV) within 72 hours. 
b  Subjects of Asian ancestry (or subjects for whom the absence of Asian ancestry cannot be confirmed) who cannot provide documentation stating that they are not carriers of 
HLA-B*1502 must give written informed consent for genotyping. Asian ancestry will be based on subject self-report. 
c  This consent for genetic saliva sample and associated questionnaire is optional. 
d  Record seizure history (the number and types of seizures that occurred over the longest available period up to 3 months prior to screening). 
e  Record all prior and concomitant medications, including over the counter medications, taken within the previous 60 days. 
f  Includes clinical chemistry, hematology and urinalysis. Estimated creatinine clearance using Cockcroft-Gault equation at Screening only. 
g  Required for subjects of Asian ancestry (or subjects for whom the absence of Asian ancestry cannot be confirmed) and who do not have documentation to show that they are not 
carriers of HLA-B*1502. 
h  Subjects who provided optional separate informed consent/assent only. 
i  A serum pregnancy test will be given to all female subjects of childbearing potential at screening. An on-site urine pregnancy test will be given to all female subjects of 
childbearing potential at Visits 1-8. Any positive urine pregnancy test will be followed up with a serum test for confirmation of pregnancy. A serum pregnancy test will be given 
to all females subjects of childbearing potential at Visit 9 (EOS) or at the EDV. 
j  The Liverpool Adverse Event Profile collects information on AEs associated with AEDs. 
k  Subjects who elect to continue on commercially available drug will not be dispensed additional ESL at this visit. Subjects who elect to discontinue ESL will be provided 
sufficient ESL to accommodate the appropriate taper regimen. 
l  Subjects will be provided with the Empatica watch and instructed in the use of the watch. 
m Subjects will be provided a standardized paper daily seizure diary and an electronic daily seizure diary and instructed in the use of the diaries. Diaries are to be completed daily 
whether a seizure occurs or not. 
n The “Baseline/Screening” (lifetime) version should be administered at the screening visit and the “Since Last Visit” version at all other time points. 
o The screening visit should take place 7 - 10 days prior to the titration visit, and may be extended to 7 – 17 days if required with consent of medical monitor. Subjects of Asian 
ancestry who require HLA-B*1502 testing (eg, do not have prior test results) may have the screening visit 7 - 17 days prior to the titration visit. 
p Subjects who discontinue prior to the EOS visit will be provided sufficient ESL to accommodate the appropriate taper regimen. 
q At the Safety Follow-Up visit, the standardized paper daily seizure diary will not be collected; however it will be reviewed as part of the subject’s safety assessments. 
 


Protocol SEP093-701, Version 3.01 
 
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2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
RESTRICTED DISTRIBUTION OF PROTOCOLS ......................................................................2 
EMERGENCY CONTACTS ..........................................................................................................3 
1. 
SYNOPSIS ...................................................................................................................4 
2. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............15 
3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................20 
4. 
INTRODUCTION ......................................................................................................23 
4.1. 
Epilepsy ......................................................................................................................23 
4.2. 
Study Conduct Rationale ............................................................................................23 
5. 
STUDY OBJECTIVES ..............................................................................................24 
5.1. 
Primary Objective .......................................................................................................24 
5.2. 
Secondary Objectives .................................................................................................24 
5.3. 
Exploratory Objectives ...............................................................................................24 
6. 
STUDY ENDPOINTS ................................................................................................25 
6.1. 
Primary Endpoint ........................................................................................................25 
6.2. 
Efficacy Endpoints ......................................................................................................25 
6.3. 
Other Endpoints ..........................................................................................................25 
6.4. 
Safety Endpoints .........................................................................................................25 
6.5. 
Exploratory Endpoints ................................................................................................26 
7. 
INVESTIGATIONAL PLAN .....................................................................................27 
7.1. 
Overall Study Design ..................................................................................................27 
7.2. 
Treatment Assignment and Blinding ..........................................................................29 
7.3. 
Rationale .....................................................................................................................29 
7.3.1. 
Rationale for the Study Design ...................................................................................29 
7.3.2. 
Rationale for the Dosages ...........................................................................................30 
7.3.3. 
Rationale for the Study Population .............................................................................30 
7.3.4. 
Rationale for the Endpoints ........................................................................................30 
8. 
SELECTION OF SUBJECTS ....................................................................................31 
8.1. 
Subject Inclusion Criteria ...........................................................................................31 


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8.2. 
Subject Exclusion Criteria ..........................................................................................31 
9. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................34 
9.1. 
Description of Study Drug ..........................................................................................34 
9.2. 
Study Drug Storage .....................................................................................................34 
9.3. 
IXRS and Dispensing of Study Drug ..........................................................................34 
9.4. 
Study Drug Accountability .........................................................................................34 
10. 
TREATMENT OF SUBJECTS ..................................................................................35 
10.1. 
Study Drug ..................................................................................................................35 
10.1.1. 
Treatment with Study Drug ........................................................................................35 
10.1.2. 
Premature Discontinuation of Treatment with Study Drug ........................................35 
10.2. 
Concomitant Antiepileptic Drugs ...............................................................................36 
10.3. 
Prior and Concomitant Medications and Therapies ....................................................36 
10.4. 
Prohibited Medications ...............................................................................................36 
10.4.1. 
Permitted Medications ................................................................................................36 
10.5. 
Guidance for Overdose ...............................................................................................37 
11. 
STUDY ASSESSMENTS ..........................................................................................38 
11.1. 
Medical History, Demographics, and Baseline Characteristics ..................................38 
11.2. 
Primary and Efficacy Assessments .............................................................................38 
11.2.1. 
Retention Rate ............................................................................................................38 
11.2.2. 
Seizures .......................................................................................................................38 
11.2.2.1. 
Seizure Classification .................................................................................................38 
11.2.2.2. 
Pre-Human Epilepsy Project Instrument ....................................................................38 
11.2.2.3. 
Seizure History ...........................................................................................................38 
11.2.2.4. 
Seizure Diaries ............................................................................................................38 
11.2.3. 
Empatica Watch ..........................................................................................................39 
11.3. 
Safety Assessments .....................................................................................................39 
11.3.1. 
Adverse Events ...........................................................................................................39 
11.3.2. 
Clinical Laboratory Tests ...........................................................................................39 
11.3.2.1. 
Safety Laboratory Tests ..............................................................................................39 
11.3.2.2. 
Urine Drug Screen ......................................................................................................40 
11.3.2.3. 
Pregnancy Testing ......................................................................................................40 
11.3.3. 
Genetic Testing ...........................................................................................................40 
11.3.3.1. 
Genetic Testing for the HLA-B*1502 Allele .............................................................40 


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11.3.3.2. 
Genetic Sampling ........................................................................................................40 
11.3.4. 
Vital Signs ..................................................................................................................40 
11.3.5. 
Electrocardiograms .....................................................................................................41 
11.3.6. 
Physical and Neurologic Examinations ......................................................................41 
11.3.7. 
Safety Scales ...............................................................................................................41 
11.3.7.1. 
Electronic Columbia-Suicide Severity Rating Scale ..................................................41 
11.3.7.2. 
The Liverpool Adverse Event Profile .........................................................................42 
11.4. 
Clinical Assessments, Quality of Life, Behavior and Mood Scales ...........................42 
11.4.1. 
EuroQol Five Dimensions Questionnaire ...................................................................42 
11.4.2. 
Clinical Global Impression – Improvement ...............................................................42 
11.4.3. 
Patient Global Impression of Change .........................................................................42 
11.4.4. 
Quality of Life in Epilepsy-Patient-Weighted ............................................................43 
11.4.5. 
POMS-Short Form ......................................................................................................43 
11.4.6. 
Neurological Disorders Depression Inventory for Epilepsy .......................................43 
11.4.7. 
The Modified Overt Aggression Scale .......................................................................43 
11.5. 
Study Visits and Assessments ....................................................................................44 
11.5.1. 
Screening: Visit 1 (-1 to -2 Week [+ 3 days]) ............................................................44 
11.5.2. 
Titration Phase: Visit 2 (Week 1, Day 1) ...................................................................45 
11.5.3. 
Start of Maintenance: Visit 3 (Week 3 ± 3 days) .......................................................45 
11.5.4. 
Visit 4 (Week 7 ± 3 days) ...........................................................................................46 
11.5.5. 
Telephone Call 1 (Week 9 ± 3 days) ..........................................................................46 
11.5.6. 
Visit 5 (Week 11 ± 3 days) .........................................................................................47 
11.5.7. 
Visit 6 (Week 15 ± 3 days) .........................................................................................47 
11.5.8. 
Telephone Call 2 (Week 17 ± 3 days) ........................................................................48 
11.5.9. 
Visit 7 and Visit 8 (Week 19 ± 3 days and Week 23 ± 3 days) ..................................48 
11.5.10. 
End of Maintenance/End of Study: Visit 9 (Week 27 ± 3 days) ................................48 
11.5.11. 
Early Discontinuation Visit ........................................................................................49 
11.5.12. 
Follow-up Visit: Visit 10 or Telephone Call 3 (Week 31 ± 7 days) ...........................50 
12. 
SAFETY REPORTING ..............................................................................................51 
12.1. 
Definitions ..................................................................................................................51 
12.1.1. 
Adverse Events ...........................................................................................................51 
12.1.2. 
Serious Adverse Events ..............................................................................................51 
12.2. 
Objective Findings ......................................................................................................52 


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12.3. 
Collection and Recording of Adverse Events .............................................................53 
12.4. 
Immediately Reportable Events ..................................................................................54 
12.4.1. 
Serious Adverse Event ................................................................................................54 
12.4.2. 
Pregnancy ...................................................................................................................55 
13. 
TERMINATION OF SUBJECT FROM STUDY ......................................................56 
14. 
STUDY TERMINATION ..........................................................................................57 
15. 
STATISTICS ..............................................................................................................58 
15.1. 
Sample Size ................................................................................................................58 
15.2. 
Analysis Populations ..................................................................................................58 
15.3. 
Data Analysis ..............................................................................................................58 
15.3.1. 
Subject Disposition .....................................................................................................58 
15.3.2. 
Drug Exposure ............................................................................................................59 
15.3.3. 
Important Protocol Deviations ....................................................................................59 
15.3.4. 
Demographics and Baseline Characteristics ...............................................................59 
15.3.5. 
Primary Analysis ........................................................................................................59 
15.3.6. 
Efficacy Analyses .......................................................................................................59 
15.3.7. 
Other Analyses ............................................................................................................60 
15.3.7.1. 
Neurological Disorders Depression Inventory for Epilepsy Score .............................60 
15.3.7.2. 
Profile of Mood States Short-form Score ...................................................................60 
15.3.7.3. 
Mood States Short-form Score ...................................................................................60 
15.3.7.4. 
Quality of Life in Epilepsy-Patient-Weighted Score ..................................................60 
15.3.7.5. 
Clinical Global Impression of Improvement Score ....................................................60 
15.3.7.6. 
Patient’s Global Impression of Change Score ............................................................60 
15.3.8. 
Safety Analyses ..........................................................................................................61 
15.3.8.1. 
Adverse Events ...........................................................................................................61 
15.3.8.2. 
Adverse Event Profile .................................................................................................61 
15.3.8.3. 
Clinical Laboratory Assessments ...............................................................................61 
15.3.8.4. 
Blood Sodium Levels .................................................................................................62 
15.3.8.5. 
Electrocardiograms .....................................................................................................62 
15.3.8.6. 
Vital Signs and Weight ...............................................................................................62 
15.3.8.7. 
Physical/Neurological Examination ...........................................................................62 
15.3.8.8. 
Concomitant Medications ...........................................................................................62 
15.3.8.9. 
Electronic Columbia-Suicide Severity Rating Scale ..................................................62 


Protocol SEP093-701, Version 3.01 
 
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15.3.9. 
Exploratory Analyses ..................................................................................................63 
15.3.10. 
Treatment of Missing Data .........................................................................................63 
16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL, DATA 
COLLECTION, MANAGEMENT, AND QUALITY ASSURANCE ......................64 
16.1. 
Data Collection/Electronic Data Capture ...................................................................64 
16.2. 
Study Monitoring ........................................................................................................64 
16.3. 
Audits ..........................................................................................................................64 
16.4. 
Study Documentation .................................................................................................65 
16.5. 
Clinical Laboratory Certification and Normal Values ................................................65 
17. 
ETHICAL AND REGULATORY OBLIGATIONS ..................................................66 
17.1. 
Study Conduct ............................................................................................................66 
17.2. 
Institutional Review Board/Independent Ethics Committee ......................................66 
17.3. 
Informed Consent .......................................................................................................67 
17.4. 
Subject Privacy ...........................................................................................................67 
17.5. 
Protocol Amendments and Emergency Deviations ....................................................67 
17.6. 
Records Retention .......................................................................................................68 
17.7. 
Inspection of Records .................................................................................................68 
17.8. 
Financial Disclosure ...................................................................................................68 
17.9. 
Publication Policy .......................................................................................................68 
18. 
REFERENCES ...........................................................................................................69 
19. 
INVESTIGATOR APPROVAL .................................................................................70 
20. 
APPENDIX I. CLINICAL LABORATORY TESTS ................................................71 
21. 
APPENDIX II. CARDIAC SAFETY MONITORING ..............................................72 
22. 
APPENDIX III. SAMPLE DAILY SEIZURE DIARY .............................................73 
 
LIST OF TABLES 
Table 1: 
Emergency Contact Information ...................................................................................3 
Table 2: 
Schedule of Assessments ............................................................................................11 
Table 3: 
List of Abbreviations ..................................................................................................20 
Table 4: 
Definition of Key Study Terms ..................................................................................22 
Table 5: 
Taper of Study Drug ...................................................................................................35 
 


Protocol SEP093-701, Version 3.01 
 
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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The abbreviations and the definition of key study terms used in the clinical study protocol are 
shown in Table 3 and Table 4. 
Table 3: List of Abbreviations 
Abbreviation 
Full Form 
AE 
Adverse event 
AED 
Anti-epileptic drugs 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
β-hCG 
Beta-human chorionic gonadotropin 
CBZ 
Carbamazepine 
CFR 
Code of Federal Regulations 
CGI-I 
Clinical Global Impression of Improvement 
CI 
Confidence Interval 
CNS 
Central nervous system 
CRF 
Case report form 
CRO 
Contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
DISCOVER 
Diagnostic Interview for Seizure Classification Outside 
of Video EEG Recording (form) 
ECG 
Electrocardiogram 
eC-SSRS 
Electronic Columbia-Suicide Severity Rating Scale 
EDV 
Early discontinuation visit 
EOS 
End of study 
EQ-5D 
EuroQol Five Dimensions Questionnaire 
ESL 
Eslicarbazepine acetate 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
HEP 
Pre-Human Epilepsy Project instrument 
HLA 
Human leukocyte antigen 
ICF 
Informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee  
ILAE 
International League Against Epilepsy 


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Table 3: 
List of Abbreviations (Continued) 
Abbreviation 
Full Form 
IPD 
Important protocol deviations 
IRB 
Institutional Review Board 
IXRS 
Interactive Web/Voice Response System 
LAEP 
Liverpool Adverse Event Profile 
LEV 
Levetiracetam 
LTG 
Lamotrigine 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent-To-Treat 
MOAS 
Modified Overt Aggression Scale 
NDDI-E 
Neurological Disorders Depression Inventory for 
Epilepsy 
OXC 
Oxcarbazepine 
PGI-C 
Patient’s Global Impression of Change 
POS 
Partial-onset seizures 
POMS-SF 
Profile of Mood States Short-form 
PPD-PVG 
PPD Pharmacovigilance  
PT 
Preferred term 
QD 
Once daily 
QOL 
Quality of life 
QOLIE-31-P 
Quality of Life in Epilepsy-Patient-Weighted (31-item) 
SAE 
Serious adverse event 
SOC 
System organ class 
SSF 
Standard seizure frequency 
T3 
Triiodothyronine  
T4 
Thyroxine 
TSH 
Thyroid stimulating hormone 
VNS 
Vagal nerve stimulation 
WBC 
White blood cell 
WHO-DRUG 
World Health Organization drug dictionary 


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Table 4: Definition of Key Study Terms  
Terms 
Definition of terms 
CRF 
A printed, optical, or electronic document designed to record all 
of the protocol required information to report to the Sponsor for 
each study subject. 
Screened Subject 
Any subject who signed the study specific informed consent and 
completed at least one study-related procedure. 
Screen Failures 
Any subject who signed the study specific informed consent but 
either failed to meet study requirements during screening or met 
study requirements at screening, but was not enrolled. 
Study Drug  
Term used for study drug provided by the Sponsor (ESL, ie, 
Aptiom). 
Treatment Period 
The period of the study in which the study drug is administered.  
Enrolled Subject 
Any subject who was successfully screened and enrolled into the 
titration period of the study. 
Completed Subject 
Any subject who completed all the Schedule of Assessments up 
to and including assessments for the end of the Maintenance 
Phase (Visit 9, the end of the study). 
Early Termination 
Subject 
Any subject who was successfully screened and entered the 
treatment period of the study, but did not complete the study. 
End of Study 
The day that the subject completes the study per the study design 
(end of the Maintenance Phase, Visit 9). 


Protocol SEP093-701, Version 3.01 
 
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4. 
INTRODUCTION 
4.1. 
Epilepsy 
Epilepsy, defined by the recurrence of spontaneous unprovoked seizures (ie, not caused by 
systemic, metabolic or toxic disorders) affects more than 50 million adults and children 
worldwide (CPMP, 2009). Globally, an estimated 2.4 million people are diagnosed with epilepsy 
each year. In high-income countries, annual new cases are between 30 and 50 per 100,000 people 
in the general population. In low-and middle-income countries, this figure can be up to two times 
higher (World Health Organization). There are no known geographic or racial differences in the 
occurrence of the disease; it occurs in both men and women and can begin at any age, but is 
more frequent in infancy, childhood, adolescence, and old age. 
The primary marker of the disease is recurrent seizures which are classified in the International 
Classification of Epileptic Seizures as generalized, partial or focal, and unclassified 
(Dreifuss, 1981). Partial seizures, which are related to a focal brain dysfunction, are the most 
frequent type (approximately 60% of cases). 
Anti-epileptic drugs (AEDs) are the major therapeutic intervention for subjects with epilepsy and 
approximately 60% of newly diagnosed patients are seizure free on a single AED. However, 
about 40% of subjects are not satisfactorily controlled and many patients suffer from significant 
adverse events (AEs) (CPMP, 2009). This lack of seizure control leads to combination therapy, 
but significant proportions of subjects continue to have regular seizures despite therapy with 
more than one AED. This suggested the need for a more selective and less toxic AED, which led 
to the development of eslicarbazepine acetate (ESL). 
4.2. 
Study Conduct Rationale 
ESL is approved for the treatment of partial-onset seizures (POS) as monotherapy or adjunctive 
therapy in adults in the US. ESL is approved in Canada as adjunctive therapy in the treatment of 
POS in patients with epilepsy who are not satisfactorily controlled with conventional therapy. 
The current open-label study is designed to investigate the use of ESL in a real-life clinical 
setting in both subjects early in the course of their disease (those using ESL as a first add-on) and 
in a treatment-resistant population (similar to those evaluated in the Phase 3 adjunctive studies). 
The treatment-resistant subjects are included in this study to assess effectiveness of ESL as a 
later adjunctive therapy in a clinical setting in order to determine if the data from Phase 3 studies 
are representative of real world treatment. In addition, there will be several additional behavioral, 
mood-related, and quality of life (QOL)-related assessments in this study that were not evaluated 
in the Phase 3 program. Therefore, this study will provide new information about the effect of 
adjunctive treatment with ESL in subjects early in the course of their disease and in treatment-
resistant subjects.  
This study will be performed in compliance with International Council for Harmonisation (ICH) 
Good Clinical Practice (GCP) guidelines and applicable local regulatory requirements. 


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5. 
STUDY OBJECTIVES 
5.1. 
Primary Objective 
The primary objective is to evaluate the effectiveness (measured by study retention rate) of ESL 
administered once daily (QD) as the first adjunctive therapy to levetiracetam (LEV) or 
lamotrigine (LTG) or as later adjunctive therapy in subjects with POS over a 24-week 
maintenance period in a real-world clinical setting. 
5.2. 
Secondary Objectives 
 To evaluate the efficacy of ESL QD as a first or later adjunctive therapy based on the 
number of seizures reported via a standardized paper daily diary over a 24-week 
maintenance period. 
 To evaluate the safety and tolerability of ESL QD as a first or later adjunctive 
therapy. 
 To evaluate the effect of treatment with ESL QD on the QOL, behavior, and mood. 
5.3. 
Exploratory Objectives 
 To evaluate the accuracy of an investigational wearable watch device from Empatica 
in recording seizure counts. 
 To evaluate the performance of an investigational electronic seizure diary in the form 
of a smartphone application (Empatica MATE). 


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6. 
STUDY ENDPOINTS 
6.1. 
Primary Endpoint 
The primary endpoint is the proportion of subjects completing 24 weeks adjunctive therapy 
during Maintenance Phase (Visit 9). 
6.2. 
Efficacy Endpoints 
 Seizure data via the paper diary will be used to calculate the following seizure related 
endpoints: 
 Standard Seizure Frequency (SSF) during the first 12 weeks, the last 12 weeks, 
and the 24 weeks of the Maintenance Phase. 
 50% and 75% responder rate (calculated as 50% and 75% reduction in SSF from 
baseline) as evaluated during the first 12 weeks, the last 12 weeks, and the 
24 weeks of the Maintenance Phase. 
 Relative reduction (%) in SSF from baseline during the first 12 weeks, the last 
12 weeks, and the 24 weeks of the Maintenance Phase. 
 Proportion of seizure-free subjects during the first 12 weeks, the last 12 weeks, 
and the 24 weeks of the Maintenance Phase. 
 Time on ESL. 
6.3. 
Other Endpoints 
 Changes from baseline in the Neurological Disorders Depression Inventory for 
Epilepsy (NDDI-E)-6-item questionnaire. 
 Changes from baseline in the Profile of Mood States Short-form (POMS-SF). 
 Changes from baseline in the agitation/behavioral measurements as evaluated by the 
Modified Overt Aggression Scale (MOAS).  
 Changes from baseline in Quality of Life in Epilepsy-Patient-Weighted 
(QOLIE-31-P) scores. 
 Change from baseline in EuroQol Five Dimensions Questionnaire (EQ-5D) scores. 
 Clinical Global Impression of Improvement (CGI-I) scores at each evaluation time 
point. 
 Patient’s Global Impression of Change (PGI-C) scores at each evaluation time point. 
6.4. 
Safety Endpoints 
 Number and percentage of subjects with AEs. 
 Number and percentage of subjects with serious adverse events (SAEs). 


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 Number and percentage of subjects with AEs leading to discontinuation. 
 Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS): Proportion (%) of 
events in each classification class (as completed by the subject). 
 Changes from baseline in clinical laboratory parameters, including thyroid panel. 
 Changes from baseline in vital signs parameters. 
 Score of AED-specific AEs (by the Liverpool Adverse Event Profile [LAEP]). 
6.5. 
Exploratory Endpoints 
 Seizure data recorded by an investigational wearable watch device from Empatica.  
 Seizure data recorded by an investigational electronic seizure diary from Empatica 
MATE application. 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design 
This is a 31-week, multicenter, 2-arm, prospective, open-label, non-randomized, Phase 4 study of 
ESL as adjunctive therapy in adult subjects with a diagnosis of epilepsy with POS. Two groups 
of ESL-naïve subjects will be evaluated. The groups are defined as follows: 
 Arm 1 (ESL as first add-on): This group will include subjects who have been 
maintained on a regimen consisting of a stable dose of LEV or LTG for at least 
1 month (28 days) prior to screening and who have not used any adjunctive treatment.  
 Arm 2 (ESL as later add-on): This group will include subjects who have been 
maintained on a regimen consisting of a stable dose of 1-2 AEDs (excluding 
oxcarbazepine [OXC]) for at least 1 month (28 days) prior to screening and who have 
used adjunctive treatment in the past. 
The Arm 1 subjects will allow an assessment of the efficacy and safety of ESL in subjects who 
are early in the course of their disease and being treated with one of the most common first line 
AEDs. The subjects in Arm 2 are similar to the subject population in the Phase 3 adjunctive 
studies, treatment-resistant subjects who are later in the course of their disease. The inclusion of 
these subjects in the present study will provide an assessment of the efficacy and safety of ESL 
as a later adjunctive therapy in a real world clinical setting. In addition, this study will provide 
data from both Arm 1 and Arm 2 for several behavioral, mood-related, and QOL-related 
assessments that were not evaluated in the Phase 3 program. 
Approximately 190 subjects will be enrolled (approximately 93 subjects in Arm 1 and 
97 subjects in Arm 2). 
The study will consist of a Screening Phase of 1 to 2 weeks, followed by a 2-week Titration 
Phase, a 24-week Maintenance Phase, and a Safety Follow-up/Taper Phase of 4 weeks. The last 
visit in the Maintenance Phase (Visit 9) is considered the End of Study (EOS) visit. 
The screening visit should take place 7 - 10 days prior to the titration visit, and may be extended 
to 7 – 17 days if required with consent of medical monitor. Subjects of Asian ancestry who 
require HLA-B*1502 testing (eg, do not have prior test results) may have the screening visit 
7 - 17 days prior to the titration visit. 
Subjects who withdraw prior to the EOS visit should have an Early Discontinuation Visit (EDV) 
within 72 hours. 
During the study, there will be 9 site visits and 2 scheduled telephone visits. The follow-up 
contact to collect information on AEs and concomitant medications may occur at a site visit or 
by a telephone call. 
The procedures and assessments performed in this study are described in Table 2. 
The study population has been selected to be similar to subjects treated in a clinical setting. The 
study will include subjects ≥ 18 years old who meet the study inclusion, do not meet exclusion 
criteria and who can provide written informed consent. In order to be eligible for participation in 
the study, subjects of Asian ancestry (or subjects for whom the absence of Asian ancestry cannot 


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be confirmed) must sign an additional genetic consent to undergo blood testing for the human 
leukocyte antigen (HLA)-B*1502 allele unless they can provide documentation of prior testing 
to confirm non-carrier status. Asian ancestry will be based on subject self-report. A full 
description of inclusion/exclusion criteria is available in Section 8. 
Signed informed consent (including genetic consent for subjects of Asian ancestry, or subjects 
for whom the absence of Asian ancestry cannot be confirmed) will be obtained prior to 
performing any study procedures.  
Subjects will complete the pre-Human Epilepsy Project (HEP) instrument at screening. The HEP 
instrument is a form administered by an Investigator to obtain a retrospective seizure history, in 
as accurate a manner as possible, in the absence of a retrospective seizure diary. The caregiver 
may contribute to the HEP data. These data will be used for seizure history only. As part of 
completing the HEP instrument, the Diagnostic Interview for Seizure Classification Outside of 
Video EEG Recording (DISCOVER) will be administered. The DISCOVER form allows 
researchers to ask subjects with epilepsy questions about the subject’s seizures in order to 
increase the likelihood of proper diagnosis and to standardize seizure classification. The intent is 
to ensure that the subject will use correct and consistent terminology to describe seizure history 
and when they complete their daily seizure diaries throughout the study. The information on the 
seizures recorded on the DISCOVER form will not be utilized for seizure analyses; it will be 
used for diagnostic and coding purposes only. Additional information on the DISCOVER form 
and the HEP instrument are available in Section 11.2.2.1 and Section 11.2.2.2, respectively. 
Seizure history at screening will be derived from the HEP. The subject will be asked about the 
number and types of seizures that occurred for the longest available period up to 3 months prior 
to screening. These data will be recorded by the Investigator on a separate seizure history case 
report form. 
During the study, the number of seizures by type will be obtained from subject entries in a 
standard paper diary and an electronic seizure diary daily starting at Visit 1 and up to Visit 9 
(EOS, the end of the 24-week Maintenance Phase). The diaries require an entry every day 
whether a seizure occurs or not. Subjects will record information for each seizure by date and 
type of seizure. A full description of the use of the seizure diaries is provided in Section 11.2.2.4. 
The subject will also be issued an investigational wearable seizure detection device at Visit 1 to 
collect exploratory data evaluating the identification of seizure activity based on skin conduction. 
The subject will wear the watch throughout the duration of the study, up to Visit 9. Additional 
details are available in Section 11.2.3. 
Eligible subjects will begin the 2-week Titration Phase on Day 1 (Week 1), during which they 
will initiate treatment with ESL 400 mg/day and remain on that dose for 1 week (Days 1 - 7). 
Subjects will titrate to ESL 800 mg/day the beginning of week 2 (Day 8) and will remain on that 
dose for 1 week up to the beginning of the maintenance phase. Subjects will maintain a 
minimum dose of 800 mg/day for the Maintenance Phase; however, during the Maintenance 
Phase, subjects may titrate in weekly increments of 400 mg/day as medically indicated at the 
discretion of the Investigator up to a maximum dose of 1200 mg/day (Canadian sites) or 
1600 mg/day (US sites) (based on maximum local labelled dose). Additional details are provided 
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Subjects who complete the 24-week Maintenance Phase may choose to continue treatment with 
commercial ESL. Subjects who chose not to continue treatment with ESL at the end of the 
Maintenance Phase will be gradually tapered off drug provided that they do not have an AE that 
requires abrupt discontinuation of the study drug. 
Subjects who prematurely discontinue treatment with ESL for any reason will be gradually 
tapered off study drug. However, abrupt discontinuation of the drug is permitted for the 
treatment of an AE. Subjects who prematurely discontinue treatment with ESL will be 
withdrawn from the study. 
Subjects should maintain their concomitant AED(s) at a constant dosage during the Titration 
Phase and Maintenance Phase of the study. However, subjects on concomitant carbamazepine 
(CBZ) may have a dose reduction (up to 25% of the total daily dose taken at study entry) in the 
last week of the Titration Phase (Week 2) or the first week of the Maintenance Phase (Week 3), 
if the subject has intolerable AEs related to an association between CBZ and ESL in the opinion 
of the Investigator. This reduction must be approved by the Medical Monitor. In addition, 
subjects taking phenytoin who experience intolerable AEs suggestive of phenytoin toxicity may 
have their dose of phenytoin reduced up to 15%, with the approval of the Medical Monitor. For 
patients who become seizure free during the trial, patients may reduce dose of baseline AEDs by 
a maximum of 25% to improve overall tolerability at the discretion of the Investigator. After the 
end of the Maintenance Phase, AEDs may be adjusted at the discretion of the Investigator. 
Subjects who are tolerant of ESL who have not had a rash or allergic reaction for at least 6 weeks 
and who provide a separate optional written genetic consent will be asked for a saliva sample for 
HLA genotyping. They will also be asked to complete a questionnaire relating to rash risk factors 
at or after Visit 4. Information from subjects who participate will be used as the control group in 
a separate rash registry study of risk associated with HLA type. 
Subjects who report a SAE of rash or other allergic reaction regardless of causality at any time 
during the study will be asked to provide consent to be contacted by the University of 
Pennsylvania on behalf of Sunovion for participation in the separate rash registry study. 
Details of the study assessments and other procedures to be performed at each visit are presented 
in Table 2, Schedule of Assessments, and Section 11, Study Assessments. If necessary, subjects 
may return to the clinic at any time for an unscheduled visit. 
7.2. 
Treatment Assignment and Blinding 
This is an open-label, and non-randomized study. Subjects will be assigned to 1 of 2 treatment 
arms defined by their prior treatment with AEDs as described for Arm 1 and Arm 2 above in 
Section 7.1. 
7.3. 
Rationale 
7.3.1. 
Rationale for the Study Design 
This study is designed to evaluate the long-term effectiveness, safety, and tolerability, (as 
measured by study retention over the 24-week Maintenance Phase) of ESL given as adjunctive 
therapy in adult subjects ≥ 18 years of age. The study will assess effectiveness and safety of ESL 
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therapy previously and in ESL-naïve subjects who have used adjunctive therapy previously, but 
are seeking additional therapeutic options. The open-label design is appropriate to assess safety 
and tolerability in this subject population. 
7.3.2. 
Rationale for the Dosages 
The ESL doses for this study have been selected based on approved adult ESL doses in the US 
(1600 mg QD) and Canada (1200 mg QD). 
7.3.3. 
Rationale for the Study Population 
This study is designed to investigate the use of ESL in a real-life clinical setting. In order to 
evaluate ESL in the type of patients encountered in clinical practice, it includes both subjects 
early in the course of their disease and in treatment-resistant subjects later in the course of their 
disease who have tried adjunctive therapy in the past. 
7.3.4. 
Rationale for the Endpoints 
The primary endpoint, retention in the study throughout the 24-week Maintenance Phase, was 
selected because both efficacy and tolerability/safety factor into the subject’s willingness to 
complete this phase of the study. Therefore, retention is a good measure of the effectiveness of 
ESL in clinical practice. 
Standard measurements are used for the evaluation of changes in seizure activity, safety and 
evaluations of quality of life, mood and behavior. 


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8. 
SELECTION OF SUBJECTS 
8.1. 
Subject Inclusion Criteria 
The subjects who fulfill the following criteria will be included in the study. 
1. Male or female subjects ≥ 18 years of age.  
2. Subject is willing and able to sign informed consent. 
3. Subject has a documented diagnosis of epilepsy with simple POS with a motor 
component or complex POS with or without secondarily generalized seizures as defined 
in the Classification of Seizures of the International League Against Epilepsy 
(ILAE, 1981). 
4. Subject has a documented electroencephalogram within 10 years prior to screening.  
5. Subject has had at least 3 POS during previous six months. 
6. Subject has had a sufficient number of seizures at time of enrollment to justify adjunctive 
therapy, as determined by the Investigator. 
7. Subjects are required to be ESL-naïve AND  
a. Maintained on a stable LEV or LTG regimen for at least 1 month (28 days) prior to 
screening with no history of adjunctive treatment (for Arm 1, ESL as first add-on). 
OR 
b. Maintained on a stable dose of 1-2 AEDs (excluding OXC) for at least 1 month 
(28 days) prior to screening and who have had prior adjunctive treatment (for Arm 2, 
ESL as later add-on). 
8. If the subject is treated with any stimulation device for epilepsy (Vagal Nerve 
Stimulation [VNS], Responsive Neurostimulator [RNS], or similar), the device must have 
been implanted at least 6 months before screening and the device parameters must be 
documented as stable for at least 1 month prior to screening. (Note: these devices will not 
be counted as concomitant AED). 
9. Except for epilepsy, subject is judged to be in general good health based on medical 
history, physical examination findings, and clinical laboratory test results. 
8.2. 
Subject Exclusion Criteria 
1. Subjects with a prior exposure to ESL. 
2. Subjects currently being treated with OXC. 
3. Subject with a history of allergic reaction to OXC or CBZ, or a history of serious allergic 
reaction (Stevens-Johnson syndrome, Drug Reaction with Eosinophilia and Systemic 
Symptoms or similar) to any AED, or a history of serious allergic reactions to other 
medications. 


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4. Subjects who have taken warfarin, felbamate, vigabatrin, or perampanel, (unless at stable 
dose with safety testing for ≥ 1 year) within a 4-week period prior to screening. 
5. Subjects taking ezogabine. 
6. Subject has taken any medication prohibited for this protocol within 4 weeks prior to 
Screening (see Section 10.4). 
7. Subjects using benzodiazepines on more than an occasional basis (defined as more than 
2 times per week), except when used chronically as an AED (see exclusion criteria 26). 
8. Seizure disorder characterized primarily by simple POS without motor signs. 
9. Subject has a history of primarily generalized seizures (eg, myoclonic, absence, tonic).  
10. Subject has a history of status epilepticus or cluster seizures (ie, 3 or more seizures within 
30 minutes) within the 3 months prior to screening.  
11. Subject has had seizures of psychogenic origin or purely subjective seizures within the 
last 2 years. 
12. Subject has had seizures too close to count accurately. 
13. Subject has a known progressive structural central nervous system (CNS) lesion, 
progressive encephalopathy, or a progressive cerebral abnormality. 
14. Subject whose current seizures are related to an acute medical illness or other 
non-epileptic origin. 
15. Subjects of Asian ancestry will be excluded if they are carriers of HLA-B*1502. Either: 
a. Subject must give written informed consent for genotyping, and test negative. 
OR  
b. Subjects must provide documentation of prior testing confirming non-carrier status. 
16. Subject has a major medical illness other than epilepsy that would prevent safe 
participation in this study, at the discretion of the Investigator, including (but not limited 
to) cardiac disease, thyroid disease, hepatic or renal impairment, endocrine or metabolic 
disease, gastrointestinal disease, or hematologic disease. Note: Active medical conditions 
that are minor or well-controlled are not exclusionary if they do not affect risk to the 
subject or the study results. If the effect of the condition in regard to the risk to the 
subject or to the study results is unclear, the Medical Monitor should be consulted. 
17. Subjects with clinically relevant laboratory abnormalities at screening (eg, sodium 
< 130 mEq/L, alanine transaminase (ALT) or aspartate transaminase (AST) > 2.0 times 
the upper limit of the normal, white blood cell [WBC] count < 3,000 cells/mm3, 
estimated creatinine clearance < 50 mL/min, or has values for thyroid testing (free 
triiodothyronine (T3), free thyroxine (T4), thyroid stimulating hormone [TSH]) 
indicating the presence of significant thyroid dysfunction. 
18. Subject has a history or presence of abnormal electrocardiogram (ECG), which in the 
Investigator’s opinion is clinically significant or QT interval corrected for heart rate using 
the Fridericia method (QTcF) of ≥ 450 msec per screening ECG. 


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19. Subject has second- or third-degree atrioventricular block that is not corrected with a 
pacemaker. 
20. Subjects who meet the Diagnostic and Statistical Manual of Mental Disorders, 5th edition 
text revision defined criteria for major depressive episode within the last 6 months. 
Subjects with mild, chronic depression without recent hospitalization who are being 
maintained on a stable dose of a single antidepressant are acceptable. 
21. Subject has an active suicidal plan or intent (in the Investigator’s opinion) in the past 
4 weeks prior to screening. 
22. Subject has a history of suicide attempt in the last 2 years prior to screening. 
23. Subject has other major psychiatric disorders. 
24. Subjects who are not able to complete the diaries in the Investigator’s opinion. 
25. Subject has a history of alcohol or substance abuse within 2 years prior to screening for 
study participation, or subjects currently using alcohol, drugs of abuse, or any prescribed 
or over-the-counter medication in a manner, which, in the opinion of the Investigator, 
indicates abuse. 
26. Subject tests positive for drugs of abuse at screening. Note: Subjects with a positive drug 
screen for marijuana, amphetamines, opiates, or benzodiazepines, who have a 
documented prescription for a medical condition and are on a stable dose of this 
prescribed medication for at least 4 weeks prior to screening, may be eligible to 
participate in the study upon approval from the Medical Monitor.  
27. Subject is pregnant, currently nursing, or intends to become pregnant during the study 
period or within 30 days of the last dose of study drug. 
28. Subject has participated in any investigational study within 30 days prior to screening, as 
documented in subject’s medical history. 
29. Subject is a clinical or investigational site staff member or relative of a staff member. 
30. Any other condition or circumstance that, in the opinion of the Investigator, may 
compromise the subject’s ability to comply with the study protocol. 


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9. 
STUDY DRUG MATERIALS AND MANAGEMENT 
9.1. 
Description of Study Drug 
Drug will be supplied as commercially available Aptiom, 400 mg tablets, 30 count bottle with an 
added supplemental study label.  
9.2. 
Study Drug Storage 
ESL acetate should be stored at the site at United States Pharmacopeia (USP) Controlled Room 
Temperature (CRT): 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 30°C 
(59°F to 86°F). Subjects should store ESL at room temperature. ESL should be kept out of reach 
and sight of children. 
9.3. 
IXRS and Dispensing of Study Drug 
An Interactive Web/Voice Response System (IXRS) will be used to register the Screening Visit 
(Visit 1) and assignment of the Subject Screening number. If the Subject is enrolled in the study 
the Screening number becomes the Subject number. The IXRS will also be utilized to register the 
Titration Visit (Visit 2), Maintenance Phase Visits (Visit 3 – Visit 9) and EDV. Study drug will 
be dispensed based on assignment by the IXRS at Visits 2 – Visit 8. At Visit 9 and EDV the 
IXRS will give an option to dispense an additional bottle of study drug if needed for taper. Please 
ensure to dispense the correct lot number(s) assigned to each Subject. In addition the IXRS will 
be utilized to register Screen Failure and Acknowledgment of study drug receipt at site. 
Specific User Manuals will be supplied. 
9.4. 
Study Drug Accountability 
The Investigator or designee will maintain accountability records, including the availability of 
study drug received, study drug dispensation and returns per Sponsor/contract research 
organization (CRO) instructions. 
The date of the first dose of study drug and the amount, the date of last dose of study drug and 
the amount, and the date of any change of study drug dose and the amount with the reason for the 
dose change for each alteration will be collected in the database. 
The Investigator or designee will collect and document the status of all used and unused study 
drug from study subjects at appropriate study visits per Sponsor/CRO instructions. 


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10. 
TREATMENT OF SUBJECTS 
10.1. 
Study Drug 
The drug dosage form will be commercial tablets of 400 mg Aptiom (ESL) in 30 count bottles 
with an added supplemental study label. 
Tablets will be taken by mouth, QD. 
Aptiom may be taken with or without food. Tablets may be crushed and mixed with food if the 
subject is incapable of swallowing a tablet. All tablets must be taken simultaneously. Subjects 
are to take study drug at approximately the same time each day. 
10.1.1. 
Treatment with Study Drug  
Eligible subjects will begin the 2-week Titration Phase on Day 1 (Week 1), during which they 
will initiate treatment with ESL 400 mg/day and remain on that dose for 1 week (Days 1 - 7). 
Subjects will titrate to ESL 800 mg/day the beginning of week 2 (Day 8) and will remain on that 
dose for 1 week up to the beginning of the maintenance phase. Subjects will maintain a 
minimum dose of 800 mg/day for the Maintenance Phase; however, during the Maintenance 
Phase, subjects may titrate in weekly increments of 400 mg/day as medically indicated at the 
discretion of the Investigator up to a maximum dose of 1200 mg/day (Canadian sites) or 
1600 mg/day (US sites) (based on maximum local labelled dose). 
During the 24-week Maintenance Phase, only one reduction to a minimum of 800 mg/day is 
permitted. Subjects requiring doses < 800 mg/day will be discontinued from the study. 
Subjects who complete the 24-week Maintenance Phase may choose to continue treatment with 
commercial ESL. Subjects who chose not to continue treatment with ESL for any reason will be 
gradually tapered off drug unless abrupt discontinuation of the drug is required in response to an 
AE. The taper schedule is provided in Table 5. 
Table 5: 
Taper of Study Drug 
Dose (mg/day) 
First Week 
Second Week 
Third Week 
800 
400 
Stop 
Stop 
1200 
800 
400 
Stop 
1600 
800 
400 
Stop 
10.1.2. 
Premature Discontinuation of Treatment with Study Drug 
Subjects who prematurely discontinue treatment with ESL prior to Visit 9 (EOS) for any reason 
will be gradually tapered off study drug (see Table 5). However, abrupt discontinuation of the 
drug is permitted for the treatment of an AE. Subjects who prematurely discontinue treatment 
with ESL (abruptly, or by taper) will be withdrawn from the study.  


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10.2. 
Concomitant Antiepileptic Drugs 
Subjects should continue treatment with their previously prescribed drugs; background 
concomitant AEDs will not be supplied by Sunovion. Subjects should maintain their concomitant 
AED(s) at a constant dosage during the Titration Phase and Maintenance Phase of the study.  
However, subjects on concomitant CBZ may have a dose reduction (up to 25% of the total daily 
dose taken at study entry) in the last week of the titration period (Week 2) or the first week of the 
Maintenance Phase (Week 3), if the subject has intolerable AEs related to association between 
CBZ and the study drug in the opinion of the Investigator. This reduction must be approved by 
the Medical Monitor. In addition, subjects taking phenytoin who experience intolerable AEs 
suggestive of phenytoin toxicity may have their dose of phenytoin reduced up to 15%, with the 
approval of the Medical Monitor. For patients who become seizure free during the trial, patients 
may reduce dose of baseline AEDs by a maximum of 25% to improve overall tolerability at the 
discretion of the Investigator. After the end of the Maintenance Phase, AEDs may be adjusted at 
the discretion of the Investigator. 
10.3. 
Prior and Concomitant Medications and Therapies 
The following information on all medication administered from screening through End of Study 
or at Early Termination will be recorded on the case report form (CRF): Medication name, dose, 
frequency, route, start date, stop date, and indication. 
Information on the format and version of coding dictionary is provided in the Data Management 
Plan. All medications will be coded using the World Health Organization drug dictionary 
(WHO-DRUG). 
10.4. 
Prohibited Medications 
The following medications are prohibited during the study. Subjects may not have taken any 
medication prohibited for this protocol within 4 weeks prior to screening. 
 OXC. 
 Warfarin, felbamate, vigabatrin, and perampanel (unless at stable dose with safety 
testing for ≥ 1 year). 
 Ezogabine. 
 Other experimental/investigational drugs taken as part of a clinical trial. 
10.4.1. 
Permitted Medications 
The following drugs and treatments are allowed 
 Vagus nerve stimulation. 
 Steroids. 
 Benzodiazepines at stable dose (as AEDs). 
 Chronic medications, other than those prohibited, taken at a stable dose. 


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 Any other drug that, in the opinion of the Investigator is necessary for the medical 
treatment of the subject, provided it is not a prohibited medication. 
10.5. 
Guidance for Overdose 
Guidance for overdose is available in the local labelling for Aptiom. 


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11. 
STUDY ASSESSMENTS 
A summary of assessments to be conducted at each visit is presented in Table 2. 
11.1. 
Medical History, Demographics, and Baseline Characteristics 
Demographic and baseline characteristics include date of birth, sex, ethnicity, race, weight, 
height, brief physical examination results, and medical history will be collected. For medical 
history, only relevant/significant medical history and recurrence of any condition will be 
collected. The collection of seizure history is discussed in Section 11.2.2. 
11.2. 
Primary and Efficacy Assessments 
11.2.1. 
Retention Rate 
The primary assessment will be retention rate, calculated as the proportion of subjects 
completing the 24-week Maintenance Phase (Visit 9). 
11.2.2. 
Seizures 
11.2.2.1. Seizure Classification 
At Screening, the Investigator will administer the Diagnostic Interview for Seizure Classification 
Outside of Video EEG Recording (DISCOVER) Form. This questionnaire is designed to allow 
researchers to ask subjects with epilepsy questions about the patient’s seizures in order to 
increase the likelihood of proper diagnosis and to standardize seizure classification. The intent is 
to ensure that the subject will use correct and consistent terminology to describe the seizures they 
are experiencing when they report their seizure history and complete their seizure diaries. The 
information on the seizures recorded on the DISCOVER form will not be utilized for seizure 
analyses; it will be used for diagnostic and coding purposes only. 
11.2.2.2. Pre-Human Epilepsy Project Instrument 
At screening, subjects will complete the HEP. The caregiver may contribute to the HEP data. 
The HEP instrument is a form administered by an Investigator to obtain a retrospective seizure 
history, in as accurate a manner as possible, in the absence of a retrospective seizure diary. These 
data will be used for seizure history only. 
11.2.2.3. Seizure History 
Seizure history at screening will be derived from the HEP. The subject will be asked about the 
number and types of seizures that occurred for the longest available period up to 3 months prior 
to screening. These data will be recorded by the Investigator on a separate seizure history case 
report form. 
11.2.2.4. Seizure Diaries 
To record seizures during the study, a standardized paper seizure diary and an electronic seizure 
diary will be dispensed at Visit 1. The subjects will be trained on use of the diaries by the site 


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personnel. The subjects will also receive a copy of the description of seizure types as presented 
in the DISCOVER form to ensure that the subject will use correct and consistent terminology to 
describe the seizures they are experiencing during the study. 
The diaries will be completed daily throughout the study, up until the end of the Maintenance 
Phase (Visit 9, EOS). The diaries require an entry on every day whether a seizure occurs or not. 
Subjects will record information for each seizure in the paper diary and electronic diary at the 
same time by date and type of seizure. At each return study visit, the seizure diaries will be 
reviewed by site staff. 
Efficacy evaluations of seizures during the study will be based on the information recorded in the 
standardized paper daily seizure diary. 
11.2.3. 
Empatica Watch 
This study will use the Embrace watch produced by Empatica. Embrace measures physiological 
data (3-axis accelerometer and gyro, skin conductance, skin temperature), runs pattern analysis, 
and issues alerts. The watch is designed such that subjects are not aware what data are 
collected/measured while they are wearing the watch.  
The subject should wear the watch on the same arm throughout the study. The watch should be 
worn on the same side of the body as the subject’s seizure focus (side of brain), if known. 
For additional details, refer to the study manual. 
11.3. 
Safety Assessments 
The Investigator or appropriate designee will review results of safety assessments on a regular 
basis and the Sponsor must be kept fully informed of any clinically significant findings either at 
screening or subsequently during study conduct. Safety assessments will be performed at the 
visits and times outlined in the Schedule of Assessments (Table 2). 
11.3.1. 
Adverse Events 
Pretreatment events will be monitored from the time informed consent form (ICF) is provided up 
until the first ESL dose administration. 
Adverse events will be collected for each subject. Adverse events will be collected at study visits 
and during telephone contact. Subjects should be queried in a non-leading manner, without 
specific prompting (eg, “Has there been any change in your health status since your last visit?”). 
See Section 12.1.1. 
AEs will be monitored from the time of first ESL dose administration. 
Serious adverse events will be monitored from the time informed consent/assent is obtained. 
11.3.2. 
Clinical Laboratory Tests 
11.3.2.1. Safety Laboratory Tests 
The clinical laboratory tests required by protocol are listed in Section 20 – Appendix I. 


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Blood and urine samples will be collected for clinical laboratory tests. All clinical laboratory 
tests will be performed centrally. For detailed instructions regarding clinical laboratory 
procedures, sampling, and shipping guidelines refer to the Central Laboratory Instructions 
Manual. Samples will be processed at a central laboratory to ensure consistency. All clinical 
laboratories will be College of American Pathologists (CAP) and Clinical Laboratory 
Improvement Amendments (CLIA) (or equivalent) certified. Any POC (point of care) kits that 
are performed on site by study personnel rather than in a lab must be CLIA waived and the study 
center must possess a CLIA certificate of Waiver. 
11.3.2.2. Urine Drug Screen 
The urine drug screen will be performed at screening. Urine will be collected at the clinical site 
in a clean container according to standard procedures. 
11.3.2.3. Pregnancy Testing 
Serum and urine pregnancy testing will be performed for female subjects as described in the 
Schedule of Assessments (Table 2). 
11.3.3. 
Genetic Testing 
11.3.3.1. Genetic Testing for the HLA-B*1502 Allele 
The HLA-B*1502 allele in individuals of Asian ancestry has been shown to be strongly 
associated with the risk of developing Stevens-Johnson syndrome when treated with CBZ. 
Because this study may include Asian subjects who may be taking CBZ, genetic testing will be 
conducted at screening in all subjects of Asian ancestry (or subjects for whom the absence of 
Asian ancestry cannot be confirmed). Genetic testing in these subjects is not required if prior 
documentation of a negative HLA-B*1502 allele test is available. 
11.3.3.2. Genetic Sampling 
Subjects who are tolerant to ESL for at least 6 weeks and who provide a separate optional written 
genetic consent will be asked to provide a saliva sample and provide additional medical history 
information. Participation is optional. Information from subjects who participate will be used as 
the control group in a separate rash registry study of risk associated with HLA type. Information 
will be de-identified and kept confidential. 
Subjects who report a SAE of rash or other allergic reaction regardless of causality at any time 
during the study will be asked to provide consent to be contacted by the University of 
Pennsylvania on behalf of Sunovion for participation in the separate rash registry study. 
11.3.4. 
Vital Signs 
Supine systolic and diastolic blood pressures, respiratory rate, pulse rate, and oral temperature 
will be measured following 5 minutes of seated rest. 
Blood pressure and pulse rate should first be taken with the subject in the supine position after 
resting for ≥ 5 minutes. Blood pressure and pulse rate will be taken again after standing for 2 to 
4 minutes. The same arm should be used during each assessment of blood pressure and pulse rate 
throughout the study. If a subject develops symptoms consistent with orthostatic hypotension 


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(light-headedness, dizziness, or changes in sensorium upon standing) at any point, his or her 
supine and standing blood pressure and pulse rate should be collected at that time in the manner 
described above. Vital signs will be obtained prior to clinical laboratory collection and 
performance of an ECG. 
11.3.5. 
Electrocardiograms 
All ECGs will be obtained in the supine position, after the subject has been resting supine for at 
least 10 minutes. ECGs will be 12-lead with a 10-second rhythm strip. ECGs should be obtained 
prior to drawing blood samples. All attempts should be made to use the same ECG recorder for 
all visits within individual subjects.  
Refer to Section 21 – Appendix II for additional information. 
11.3.6. 
Physical and Neurologic Examinations 
A brief physical examination, assessing the subject’s overall health and physical condition, will 
be performed according to the site’s standard operating procedures. A brief neurological 
examination will also be conducted. These examinations will occur at screening and at the time 
points indicated in Table 2. 
11.3.7. 
Safety Scales 
11.3.7.1. Electronic Columbia-Suicide Severity Rating Scale 
The Columbia-Suicide Severity Rating Scale (C-SSRS) is a tool designed to systematically 
assess and track suicidal AEs (suicidal behavior and suicidal ideation). The electronic Columbia-
Suicide Severity Rating Scale (eC-SSRS) is a computer-automated, subject-reported version of 
the C-SSRS, in which the subject’s response to a question prompts and shows the appropriate 
follow-up questions (if any). 
The strength of this suicide classification system is in its ability to comprehensively identify 
suicidal events while limiting the over-identification of suicidal behavior. The eC-SSRS scale 
takes approximately 5 minutes to administer. Occurrence of suicidal ideation is defined as having 
answered “yes” to at least one of the 5 suicidal ideation sub-categories (wish to be dead, non-
specific active suicidal thoughts, active suicidal ideation with any methods [not plan] without 
intent to act, active suicidal ideation with some intent to act [without specific plan], and active 
suicidal ideation with specific plan and intent) at any evaluation. Occurrence of suicidal behavior 
is defined as having answered “yes” to at least one of the 4 suicidal behavior sub-categories 
(actual attempt, interrupted attempt, aborted attempt, and preparatory acts or behavior) at any 
post-baseline evaluation. 
The “Baseline/Screening” (lifetime) version should be administered at the screening visit and the 
“Since Last Visit” version at all other time points. 
Subjects who express suicidal ideation or behavior in completion of the eC-SSRS during the 
course of the study should be evaluated by the investigator and referred to a mental health 
professional at the discretion of the investigator. 


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11.3.7.2. The Liverpool Adverse Event Profile 
The LAEP is designed as a patient self-report scale to assess the frequency of AED side effects. 
It includes 19 items rated on a 4-point Likert scale with 1, never a problem; 2, rarely a problem; 
3, sometimes a problem; and 4, always a problem. Total scores range from 19 to 76, with high 
scores indicating more-frequent symptom reporting. 
The LAEP is introduced to the participants in the questionnaire with the heading “Here are a few 
questions about your health generally.” The recommended preamble to the scale followed with 
the words, “During the last 4 weeks, have you had any of the problems listed.” The problems 
include unsteadiness, tiredness, restlessness, feelings of anger or aggression to others, 
nervousness and/or agitation, headache, hair loss, problems with skin (eg, acne, rash), double or 
blurred vision, upset stomach, difficulty in concentrating, trouble with mouth or gums, shaky 
hands, weight gain, dizziness, sleepiness, depression, memory problems, and disturbed sleep.  
No indication is given within the questionnaire that the symptoms listed might be linked to the 
use of medication. 
11.4. 
Clinical Assessments, Quality of Life, Behavior and Mood Scales 
11.4.1. 
EuroQol Five Dimensions Questionnaire 
The EQ-5D is made up of 2 components; health state description and overall health evaluation.  
In the description part, health status is measured in terms of five dimensions (5D); mobility, 
self-care, usual activities, pain/discomfort, and anxiety/depression. Mobility dimension asks 
about the person’s walking ability. Self-care dimension asks about the ability to wash or dress by 
oneself, and usual activities dimension measures performance in “work, study, housework, 
family or leisure activities.” In pain/discomfort dimension, it asks how much pain or discomfort 
they have, and in anxiety/depression dimension, it asks how anxious or depressed they are. The 
respondents self-rate their level of severity for each dimension using a 5-level scale. 
In addition, the respondents evaluate their overall health status using the visual analogue scale. 
11.4.2. 
Clinical Global Impression – Improvement 
The CGI-I scale is a 7-point scale that requires an approved rater to assess how much the 
patient’s illness has improved or worsened relative to a baseline state at the beginning of the 
intervention and rated as: 1, very much improved; 2, much improved; 3, minimally improved; 
4, no change; 5, minimally worse; 6, much worse; or 7, very much worse. 
11.4.3. 
Patient Global Impression of Change 
The PGI-C is a 7-point scale that requires the subject to assess the change (if any) in activity 
limitations, symptoms, emotions and overall quality of life since treatment. The subject 
responses include 1) no change (or condition has gotten worse), 2) almost the same, hardly any 
change at all, 3) a little better, but no noticeable change, 4) somewhat better, but the change has 
not made any real difference, 5) moderately better, and a slight but noticeable change, 6) better, 
and a definite improvement that has made a real and worthwhile difference or 7) a great deal 
better, and a considerable improvement that has made all the difference. 


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11.4.4. 
Quality of Life in Epilepsy-Patient-Weighted  
The QOLIE-31-P contains seven multi-item scales that investigate the following health concepts: 
emotional well-being, social functioning, energy/fatigue, cognitive functioning, seizure worry, 
medication effects and overall QOL. The QOLIE-31-P overall score is obtained using a weighted 
average of the multi-item scale scores. 
11.4.5. 
POMS-Short Form 
The POMS-SF is an instrument designed to assess transient, distinct mood states and consists of 
a list of 37 adjectives. Respondents indicate the degree to which each adjective describes 
themselves during the last week using a 5-point Likert scale. This format yields both an overall 
Total Mood Disturbance score as well as scores for each of the six subscales contained in the 
original POMS: Fatigue-Inertia, Vigor-Activity, Tension-Anxiety, Depression-Dejection, 
Anger-Hostility, and Confusion-Bewilderment. The items included in the short form scales are: 
Depression = unhappy, sad, blue, hopeless, discouraged, miserable, helpless, worthless; 
Vigor = lively, active, energetic, cheerful, full of pep, vigorous; Confusion = confused, unable to 
concentrate, bewildered, forgetful, uncertain about things; Tension = Tense, on edge, uneasy, 
restless, nervous, anxious; Anger = angry, peeved, grouchy (written as grovely in some versions), 
annoyed, resentful, bitter, furious; Fatigue = worn-out, fatigued, exhausted, weary, bushed. 
11.4.6. 
Neurological Disorders Depression Inventory for Epilepsy 
The NDDI-E is a 6-item questionnaire validated to screen for depression in people with epilepsy. 
The NDDI-E consists of the following items:  
 Everything is a struggle. 
 Nothing I do is right.  
 Feel guilty. 
 I’d be better off dead. 
 Frustrated. 
 Difficulty finding pleasure. 
Each item is rated on a 4-point Likert scale with higher scores indicating a more severe response. 
11.4.7. 
The Modified Overt Aggression Scale 
The MOAS is a 4-part behavior rating scale designed to measure four types of aggressive 
behavior as witnessed in the past week. The MOAS will be completed by an approved rater. 
Each section consists of 5 questions, with the first section regarding verbal aggression, the 
second section focusing on aggression against property, the third section measuring 
autoaggression, and the fourth section concerning physical aggression. Respondents are asked to 
check whether each statement describes behavior over the previous week. 
Total scores on the MOAS range from 0-40, with a higher score indicating more aggressive 
behavior. Each checked statement receives 1 point, then points from each section are summed. 
Section scores are weighted as follows: 


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Scores from the “Aggression Against Property” section multiplied by 2; Scores from the 
“autoaggression” section multiplied by 3; Scores from the “physical aggression” section 
multiplied by 4. Weighted scores are then added together to yield the total score. 
11.5. 
Study Visits and Assessments 
11.5.1. 
Screening: Visit 1 (-1 to -2 Week [+ 3 days]) 
Subjects will be evaluated at the Screening Visit over the 1- to 2-week Screening Phase to 
determine their eligibility to enroll in the study. The screening visit should take place 7 – 10 days 
prior to the titration visit, and may be extended to 7 – 17 days if required with consent of medical 
monitor. Subjects of Asian ancestry who require HLA-B*1502 testing (eg, do not have prior test 
results) may have the screening visit 7 - 17 days prior to the titration visit. 
Subjects are assigned screening numbers sequentially utilizing the IXRS system. 
The following study-related procedures will be performed at screening: 
 Obtain signed informed consent for study participation prior to performing any study 
procedures. 
 Obtain signed genetic consent for genotyping in subjects of Asian ancestry (or 
subjects for whom the absence of Asian ancestry cannot be confirmed) from the 
subject before conducting any other visit procedures. Note: This consent is not 
required for subjects who can provide documentation of prior testing to confirm 
non-carrier status. 
 Obtain genetic consent for optional saliva HLA testing. 
 Review inclusion/exclusion criteria. 
 Record demographics. 
 Record medical/neurologic history. 
 Complete DISCOVER form. 
 Administer HEP Instrument and collect data. 
 Record seizure history (the number and types of seizures that occurred for the longest 
available period up to 3 months prior to screening). 
 Record previous medication and concomitant medications including over the counter 
medications taken within the previous 2 months. 
 Perform physical and neurological examination. 
 Obtain vital signs, body weight, and height. 
 Perform a 12-lead ECG. 
 Obtain blood and urine samples for clinical laboratory evaluation (serum chemistry, 
hematology, urinalysis, and thyroid panel). 
 Obtain urine for urine drug screen (UDS). 


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 Obtain blood sample for HLA-B*1502 testing (subjects of Asian ancestry only, or 
subjects for whom the absence of Asian ancestry cannot be confirmed). Note: Not 
required for subjects who can provide documentation of prior testing to confirm non-
carrier status. 
 For females of childbearing potential, obtain blood for serum beta-human chorionic 
gonadotropin (β-hCG). 
 Record pre-treatment AEs. 
 Distribute seizure diaries and instruct the subject in the use of the diaries. 
 Distribute Empatica watch and instruct the subject on the use of the watch. 
 Administer the eC-SSRS questionnaire. 
11.5.2. 
Titration Phase: Visit 2 (Week 1, Day 1) 
 Review of inclusion/exclusion criteria. 
 Record concomitant medications. 
 Obtain vital signs and body weight. 
 For females of childbearing potential, obtain sample for urine pregnancy test (to be 
confirmed with serum pregnancy test if positive). 
 Record LAEP. 
 Record AEs. 
 Dispense study drug. 
 Collect paper seizure diary. 
 Distribute paper seizure diary. 
 Review seizure diaries. 
 Administer questionnaires (EQ-5D, QOLIE-31, POMS-SF, NDDI-E, MOAS, and 
eC-SSRS). 
11.5.3. 
Start of Maintenance: Visit 3 (Week 3 ± 3 days) 
 Record concomitant medications.  
 Perform physical and neurological examination. 
 Obtain vital signs and body weight. 
 For females of childbearing potential, obtain sample for urine pregnancy test (to be 
confirmed with serum pregnancy test if positive). 
 Record LAEP. 
 Record AEs. 
 Dispense study drug. 


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 Collect study drug. 
 Record any ESL dose change since the last study visit. 
 Record any AED dose change since the last study visit. 
 Collect paper seizure diary. 
 Distribute paper seizure diary. 
 Review seizure diaries. 
 Administer the questionnaires (CGI-I, PGI-C, and eC-SSRS). 
11.5.4. 
Visit 4 (Week 7 ± 3 days) 
 Record concomitant medications. 
 Perform physical and neurological examination. 
 Obtain vital signs and body weight. 
 Collect a saliva sample for characterization of HLA and Questionnaire (optional, for 
subjects who have signed optional genetic consent and who have been tolerant of 
ESL without rash or allergic reaction for at least 6 weeks). 
 For females of childbearing potential, obtain sample for urine pregnancy test (to be 
confirmed with serum pregnancy test if positive). 
 Record LAEP.  
 Record AEs. 
 Dispense study drug. 
 Collect study drug. 
 Record any ESL dose change since the last study visit. 
 Record any AED dose change since the last study visit. 
 Collect paper seizure diary. 
 Distribute paper seizure diary. 
 Review seizure diaries. 
 Administer the eC-SSRS questionnaire. 
11.5.5. 
Telephone Call 1 (Week 9 ± 3 days) 
 Record AEs. 
 Record any ESL dose change since the last study visit. 
 Record any AED dose change since the last study visit. 


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11.5.6. 
Visit 5 (Week 11 ± 3 days) 
 Record concomitant medications. 
 Perform physical and neurological examination. 
 Obtain vital signs and body weight. 
 For females of childbearing potential, obtain sample for urine pregnancy test (to be 
confirmed with serum pregnancy test if positive). 
 Record LAEP. 
 Record AEs. 
 Dispense study drug. 
 Collect study drug. 
 Record any ESL dose change since the last study visit. 
 Record any AED dose change since the last study visit.  
 Collect paper seizure diary. 
 Distribute paper seizure diary. 
 Review seizure diaries. 
 Administer questionnaires (EQ-5D, CGI-I, PGI-C, QOLIE-31, POMS-SF, NDDI-E, 
MOAS, and eC-SSRS). 
11.5.7. 
Visit 6 (Week 15 ± 3 days) 
 Record concomitant medications. 
 Perform physical and neurological examination. 
 Obtain vital signs and body weight. 
 For females of childbearing potential, obtain sample for urine pregnancy test (to be 
confirmed with serum pregnancy test if positive). 
 Record LAEP. 
 Record AEs. 
 Dispense study drug. 
 Collect study drug. 
 Record any ESL dose change since the last study visit. 
 Record any AED dose change since the last study visit.  
 Collect paper seizure diary. 
 Distribute paper seizure diary. 
 Review seizure diaries. 


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 Administer the eC-SSRS questionnaire. 
11.5.8. 
Telephone Call 2 (Week 17 ± 3 days) 
 Record AEs. 
 Record any ESL dose change since the last study visit. 
 Record any AED dose change since the last study visit. 
11.5.9. 
Visit 7 and Visit 8 (Week 19 ± 3 days and Week 23 ± 3 days) 
 Record concomitant medications. 
 Perform physical and neurological examination (Visit 8 only). 
 Obtain vital signs and body weight. 
 For females of childbearing potential, obtain sample for urine pregnancy test (to be 
confirmed with serum pregnancy test if positive). 
 Record LAEP. 
 Record AEs. 
 Dispense study drug. 
 Collect study drug. 
 Record any ESL dose change since the last study visit. 
 Record any AED dose change since the last study visit.  
 Collect paper seizure diary   
 Distribute paper seizure diary 
 Review seizure diaries. 
 Administer the eC-SSRS questionnaire. 
11.5.10. 
End of Maintenance/End of Study: Visit 9 (Week 27 ± 3 days) 
 Record concomitant medications. 
 Perform physical and neurological examination. 
 Obtain vital signs and body weight. 
 Perform a 12-lead ECG. 
 For females of childbearing potential, obtain blood for serum β-hCG. 
 Obtain blood sample and urine sample for clinical laboratory testing (including 
thyroid panel). 
 Record LAEP. 
 Record AEs. 


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 Dispense study drug if needed for taper (Note: Subjects who elect to continue on 
commercially available drug will not be dispensed additional ESL at this visit. 
Subjects who elect to discontinue ESL will be provided sufficient ESL to 
accommodate the appropriate taper regimen.) 
 Collect study drug. 
 Record any ESL dose change since the last study visit. 
 Record any AED dose change since the last study visit.  
 Collect paper seizure diary   
 Distribute paper seizure diary 
 Review seizure diaries. 
 Administer questionnaires (EQ-5D, CGI-I, PGI-C, QOLIE-31, POMS-SF, NDDI-E, 
MOAS, and eC-SSRS). 
 Ensure return of watch and data collection device. 
11.5.11. 
Early Discontinuation Visit 
Subjects who withdraw prior to the EOS visit should have an early discontinuation visit (EDV) 
within 72 hours. Every effort should be made for all subjects prematurely discontinuing the study 
drug, regardless of cause, to undergo final evaluation described below:  
 Record concomitant medications. 
 Perform physical and neurological examination. 
 Obtain vital signs and body weight. 
 Perform a 12-lead ECG. 
 For females of childbearing potential, obtain blood for serum β-hCG. 
 Obtain blood and urine sample for clinical laboratory testing (including thyroid 
panel). 
 Record LAEP. 
 Record AEs. 
 Collect study drug. 
 Record any AED dose change since the last study visit. 
 Collect paper seizure diary  
 Distribute paper seizure diary 
 Review seizure diaries. 
 Administer questionnaires (EQ-5D, CGI-I, PGI-C, QOLIE-31, POMS-SF, NDDI-E, 
MOAS, and eC-SSRS). 
 Dispense study drug if needed for taper. 
 Ensure return of watch and data collection device. 


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11.5.12. 
Follow-up Visit: Visit 10 or Telephone Call 3 (Week 31 ± 7 days) 
 Record AEs. 
 Record concomitant medications. 
 Review paper seizure diary. 


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12. 
SAFETY REPORTING 
12.1. 
Definitions 
12.1.1. 
Adverse Events 
An AE is any untoward medical occurrence temporally associated with the use of a drug in 
humans, whether or not considered drug related. 
Untoward medical occurrences that occur between the time of signing the ICF and first drug 
administration are pre-treatment events. Those that occur after first administration of study drug 
are considered AEs. 
An AE can, therefore, be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease occurring after the administration of a medicinal (investigational) 
product, whether or not considered related to the medicinal (investigational) product. AEs may 
include the onset of new illness and the exacerbation of pre-existing conditions. 
In this study, seizures should not routinely be considered as AEs. Individual seizures (including 
clusters of seizures and status epilepticus) which are sufficiently severe to require intervention 
beyond what is usual for the subject or hospitalization may be recorded as AEs. Worsening of 
seizures (either in severity, pattern, type, or frequency) and injury or other adverse consequences 
of seizures should be recorded as AEs. 
The Investigator should attempt to establish a diagnosis of the event based on signs, symptoms, 
and/or other clinical information. In such cases, the diagnosis should be documented as the AE 
and not the individual signs/symptoms. 
12.1.2. 
Serious Adverse Events 
A SAE is an AE that meets one or more of the following criteria: 
 Results in death. 
 Is life-threatening. 
 Requires hospitalization or prolongation of existing hospitalization. 
 Results in persistent or significant disability or incapacity. 
 Is a congenital anomaly or birth defect. 
 Is an important medical event that may jeopardize the subject or may require a 
medical or surgical intervention to prevent one of the outcomes listed above. 
Examples of such medical events include allergic bronchospasm requiring intensive 
treatment in an emergency room or at home, or blood dyscrasias. 
The term “severe” is often used to describe the severity of a specific event (as in mild, moderate, 
or severe myocardial infarction) (see Section 12.3); the event itself, however, may be of 
relatively minor medical significance (such as severe headache). This is not the same as 
“serious,” which is based on subject/event outcome or action criteria usually associated with 
events that pose a threat to a subject's life or functioning as defined by the criteria above. 


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During the study, if a subject has a hospitalization or procedure (eg, elective surgery) that was 
scheduled before the study entry, ie, before informed consent for an event/condition that 
occurred before the study, the hospitalization is considered a therapeutic intervention and not the 
result of a SAE. However, if the event/condition worsens during the study, it should be reported 
as an AE (or SAE, if the event/condition results in a serious outcome such as prolongation of 
hospitalization). 
Life-threatening means that the subject was, in the view of the Investigator, at immediate risk of 
death from the event as it occurred. This definition does not include an event that had it occurred 
in a more severe form might have caused death. 
SAE criteria information will be captured on the CRF. 
12.2. 
Objective Findings 
Clinically significant abnormal objective findings (eg, clinical laboratory value, ECG value, and 
physical examination observation) will also be recorded as AEs. 
When a clear diagnosis is available that explains the objective findings, this diagnosis will be 
recorded as the AE, and not the abnormal objective finding (eg, viral hepatitis will be recorded as 
the AE, not transaminase elevation). If a definite diagnosis is not available, then record the sign 
(eg, clinically significant elevation of transaminase levels) or symptom (eg, abdominal pain) as 
the AE. 
Clinical laboratory test results will be reviewed by the Investigator. The Investigator must 
determine the clinical significance of all out of range values. Clinical laboratory tests with 
possibly drug related or clinically relevant abnormal values of uncertain causality may be 
repeated. Any abnormal values that persist should be followed at the discretion of the 
Investigator. The Investigator will document that he/she has reviewed laboratory tests (for paper 
reports: initial and date all pages; for electronic reports: document in electronic system or add 
separate comment to CRF). 
Clinical Laboratory Tests Outside the Normal Range: Any value outside the normal range will be 
flagged for the attention of the Investigator or appropriate designee at the study center. The 
Investigator or appropriate designee will indicate whether or not the value is of clinical 
significance. If the result of any test (or repeat test, if done) from the samples taken during 
screening is indicated as clinically significant and is not covered by the inclusion criteria in 
Section 8.1, the subject will not be allowed into the study. Additional testing during the study 
may be done if medically indicated. If a clinically significant abnormality is found in the samples 
taken after dosing, during the study, and/or at the EOS/EDV Visit, this should be recorded as an 
AE and the subject will be followed until the test(s) has (have) normalised or stabilised. 
All on-site ECG tracings will be reviewed by the Investigator. The Investigator must determine 
the clinical significance of all abnormal ECGs. ECG with possibly drug-related or clinically 
relevant abnormal findings of uncertain causality may be repeated. Any abnormal ECGs that 
persist should be followed at the discretion of the Investigator. ECG tracings will be initialed and 
dated on all pages by the Investigator. 


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12.3. 
Collection and Recording of Adverse Events 
All pre-treatment events and AEs must be recorded in the subject’s study records/source 
documents. All pre-treatment events must be recorded on the CRF. All AEs must be recorded on 
the CRF from first dose administration through the final study visit. All SAEs must be recorded 
on the CRF from the time informed consent/assent is obtained through the final study visit. 
All AEs will be followed until resolution, stabilization of the condition, the event is otherwise 
explained, or the subject is lost to follow-up. 
Each AE is to be evaluated for duration, severity, frequency, seriousness, action taken with the 
study treatment, outcome, and causal relationship to the study treatment. Definitions for severity, 
frequency, action taken with the study treatment, outcome, and causal relationship to the study 
treatment are presented below. 
The severity of AE: 
 Mild – Ordinarily transient symptoms that do not influence performance of subject’s 
daily activities. Other treatment is not ordinarily indicated. 
 Moderate – Marked symptoms sufficient to make the subject uncomfortable. 
Moderate influence on performance of subject’s daily activities. Other treatment may 
be necessary. 
 Severe – Symptoms cause considerable discomfort. Substantial influence on subject’s 
daily activities. May be unable to continue the study, and other treatment may be 
necessary. 
The frequency of AE: 
 Once – an isolated episode. 
 Intermittent – occurs on 2 or more separate occasions. 
 Continuous – does not abate from date of onset to date of resolution. 
The action taken with the study treatment: 
 Drug Interrupted – Study drug stopped temporarily. 
 Drug Withdrawn – Study drug stopped permanently. 
 Dose Reduced. 
 Dose Increased. 
 Dose Not Changed. 
 Not Applicable. 
 Unknown. 
The outcome of the AE: 
 Recovered/Resolved. 
 Recovering/Resolving. 


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 Not Recovered/Not Resolved. 
 Recovered/Resolved with Sequelae. 
 Fatal. 
 Unknown. 
The causal relationship of the AE to the study treatment:  
 Not related 
  Not related – Improbable temporal relationship and is plausibly related to other 
drugs or underlying disease. 
 Related 
 Possible – occurred in a reasonable time after study drug administration, but 
could be related to concurrent drugs or underlying disease. 
 Probable – occurred in a reasonable time after study drug administration, is 
unlikely to be attributable to concurrent drugs or underlying disease, and there is a 
plausible mechanism to implicate the study drug. 
 Definite – occurred in a reasonable time after study drug administration and 
cannot be explained by concurrent drugs or underlying disease. The adverse event 
should respond to dechallenge/rechallenge, however, this is not mandatory before 
assigning a definite causality. 
The Medical Monitor is the initial contact person for protocol-related questions or discussion of 
AEs. The contact information for the Medical Monitor as well as other emergency contact 
information can be found in Table 1 of this protocol. 
12.4. 
Immediately Reportable Events 
The following medical events must be immediately reported to the Sponsor: 
 SAE. 
 Pregnancy. 
Emergency contact information can be found in Table 1. 
12.4.1. 
Serious Adverse Event 
If the Investigator or study center staff becomes aware of a SAE that occurs in a study subject 
after obtaining informed consent through 30 days following the last dose of the study 
medication, this must be reported immediately to the Sponsor whether considered related or 
unrelated to the study drug. SAEs must be recorded on the CRF and the data recorded should 
agree with that on the SAE form. 
SAEs will be followed until resolution, loss to follow-up, stabilization of condition, or the event 
is otherwise explained. 
In addition to the initial telephone notification, an initial SAE form as applicable must be 
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(PPD-PVG) within 1 business day of the Investigator or study center staff becoming aware of the 
event. The SAE form must be signed by the Investigator or appropriate designee. PPD-PVG 
provides the SAE form used to report SAEs. 
The Sponsor or designee will promptly notify all study centers and Investigators of a SAE that is 
determined to be expedited to the Regulatory Authorities in accordance with applicable law(s) 
and regulation(s). These SAEs must be promptly reported to the Institutional Review Board 
(IRB) or Independent Ethics Committee (IEC) by the Principal Investigator or the appropriate 
person at the study center if required per IRB/IEC guidelines. 
If an SAE is reported after participation of the study, the Investigator or an authorized delegate 
should report SAEs “spontaneously” to PPD-PVG if considered at least possibly related to the 
study drug. 
12.4.2. 
Pregnancy 
Pregnancies that occur from the time that informed consent is signed through 30 days following 
the last dose of the study medication will be collected and reported on the Pregnancy Event Form. 
If a subject or a subject’s partner becomes pregnant during the course of the study, they will be 
instructed to report the pregnancy to the Investigator (see below). All female pregnant subjects 
will be instructed to commence discontinuation of the study medication. Further, the subject (or 
female partner of male subject) will be requested to return promptly/within 48 hours of the first 
notification of pregnancy to the study center and undergo a serum/urine pregnancy test, as 
confirmation of pregnancy. If positive, the female pregnant subject will no longer receive any 
additional study medication. All pregnancies, whether or not the subject received any additional 
study medication, will be followed until resolution (ie, termination [voluntary or spontaneous] or 
birth). 
To report a pregnancy, the Pregnancy Event Form must be completed and sent via fax to 
PPD- PVG within 1 business day of the Investigator or study center staff becoming aware of the 
pregnancy. The Sponsor provides the Pregnancy Event Form. 
Pregnancy itself is not regarded as an AE unless there is a suspicion that the study drug may have 
interfered with the effectiveness of a contraceptive medication or other AEs were detected. 


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13. 
TERMINATION OF SUBJECT FROM STUDY 
Subjects may terminate the study participation at any time for any reason. 
Subjects may be discontinued from the study at any time for any of the following reasons: 
 Adverse event. 
 Lack of efficacy (specify). 
 Withdrawal by subject (specify).  
 Withdrawal by Investigator (specify). 
 Protocol deviation (specify). 
 Study terminated by Sponsor. 
 Death. 
 Pregnancy (subject or subject’s partner). 
 Other (specify). 
If at any time during the course of the study, in the opinion of the Investigator, the subject may 
no longer safely participate due to a change in medical status (eg, experiences an AE, becomes 
pregnant), the subject must be discontinued from the study. 
Subjects may discontinue the study at any time due to worsening of seizures, intolerability, or 
other reasons. 
Subjects who discontinue the study will undergo taper of study drug, unless abrupt 
discontinuation of the drug is required in response to an AE (eg, rash). 
Subjects who experience an intolerable AE at the lowest dose, or who are unwilling to attempt a 
dose reduction within the allowed range, will be discontinued from the study. 
The reason and information for study drug discontinuation will be recorded on the appropriate 
CRF. 
Subjects who prematurely terminate the study participation will not be replaced. 
Every effort should be made for all subjects prematurely discontinuing the study drug, regardless 
of cause, to undergo final evaluation procedures described in Section 11.5.11. 


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14. 
STUDY TERMINATION 
The Sponsor reserves the right to discontinue the study at this study center or at multiple centers 
for safety or administrative reasons at any time while safeguarding that early termination does 
not compromise subjects’ safety or well-being. In particular, a study center that does not recruit 
at an acceptable rate may be closed. Should the study be terminated and/or the study center 
closed for whatever reason, all documentation must be returned to the Sponsor or its 
representative. 
If, in the opinion of the Investigator, clinical observations suggest it may be unsafe to continue, 
the Investigator may terminate part or the entire study after consultation with the Sponsor. 


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15. 
STATISTICS 
15.1. 
Sample Size  
Sample size is calculated based on the precision (a half width of the 95% confidence interval 
[CI]) for the estimate of the completion rate as assumed as below and is used the Normal 
approximation to the Binomial distribution. 
Arm 1 (first add-on): Assuming a completion rate of 60% at 24 weeks of the Maintenance Phase 
for Arm 1, to show the lower limit of the 95% CI in the rate to be 50% (50%, 70%), the sample 
size is estimated at approximately 93 subjects. 
Arm 2 (later add-on): Assuming the completion rate of 50% at 24 weeks of the Maintenance 
Phase for Arm 2, to show the lower limit of the 95% CI in the rate to be 40% (40%, 60%), the 
sample size is estimated at approximately 97 subjects.  
Total estimated subject enrollment is approximately 190 subjects. 
15.2. 
Analysis Populations 
The safety population will consist of all subjects who have taken any study medication and will 
be used for all analyses except efficacy analyses.  
The modified intent-to-treat (mITT) population will include subjects who are in the safety 
population and have available seizure data. The mITT population will be used for efficacy 
analyses. 
15.3. 
Data Analysis 
The Statistical Analysis Plan provides details on the statistical methods planned for this study 
and will be finalized prior to the database lock. Statistical summaries described in sections below 
will primarily be provided for all subjects (ie, overall summary) in the analysis populations of 
interest unless otherwise stated. 
All endpoints will be summarized descriptively for Arm 1 and Arm 2 separately. There will be 
no statistical comparisons between Arm 1 and Arm 2. 
For the efficacy endpoints, baseline will be defined as the seizure data for the longest available 
period up to 3 months prior to screening from seizure history and from screening to first dose of 
study medication from the paper seizure diary. 
For all other endpoints, baseline will be defined as the last non-missing measurement taken prior 
to the first dose of study drug administration. 
15.3.1. 
Subject Disposition  
Subject disposition will be summarized and presented for the number and percentage of subjects, 
who were screened, screen-failed, completed the study, and discontinued early (including 
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15.3.2. 
Drug Exposure 
The number of doses taken as well as the extent of exposure will be summarized with descriptive 
statistics and presented. For each subject, the number of doses taken will be computed. The 
extent of exposure will be computed as the number of days from the first exposure to study drug 
to the last exposure to study drug, ignoring missing days. Average daily dose will also be 
calculated. 
15.3.3. 
Important Protocol Deviations 
Important protocol deviations (IPDs) will be identified and documented based on a review of 
potentially IPDs. The potentially IPDs will be identified shortly before database lock, either 
through programmatic checks of study data (eg, inclusion/exclusion criteria violations), as well 
as through review of selected data listings (eg, Investigator comments, concomitant 
medications). The potentially IPDs to be reviewed include, but are not limited to, subjects who: 
 Did not meet inclusion/exclusion criteria or eligibility was not adequately verified. 
 Received any prohibited concomitant medication. 
 Developed study withdrawal criteria but were not withdrawn. 
Individual IPDs will be presented in a data listing. The number and percentage of subjects with 
IPDs will be summarized by type of deviation as categorized above. 
15.3.4. 
Demographics and Baseline Characteristics 
Demographics, including (age, gender, race, and ethnicity where applicable), and other baseline 
characteristics collected at screening, such as height, weight, body mass index, and disease 
conditions will be summarized using descriptive statistics. These data will be presented as a 
listing. 
15.3.5. 
Primary Analysis 
The proportion of subjects completing 24 weeks adjunctive therapy during Maintenance Phase 
and the 95% CI will be calculated for Arm 1 and Arm 2 separately. 
15.3.6. 
Efficacy Analyses 
All efficacy endpoints will be summarized descriptively in this study. Changes in efficacy 
parameters will be calculated with reference to the baseline, defined as the seizure data for the 
longest available period up to 3 months prior to screening from seizure history and from 
screening to first dose of study medication from the paper seizure diary. 
All seizure related endpoints will be calculated based on the data from the paper diary. 
Seizure frequency will be standardized to 28-day rate. The SSF and changes from baseline will 
be summarized during the first 12 weeks, the last 12 weeks, and the 24 weeks of the 
Maintenance Phase.  
Two responder rates (50%, and 75% responder rates) are defined as subjects who have ≥ 50%, 
and subjects who have ≥ 75% reduction in SSF from baseline, respectively. The proportions of 


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responders in each rate will be summarized during the first 12 weeks, the last 12 weeks, and the 
24 weeks of the Maintenance Phase. 
Relative reduction (%) in SSF from baseline will be calculated during the first 12 weeks, the last 
12 weeks, and the 24 weeks of the Maintenance Phase. 
The proportion (%) of seizure-free subjects will be provided during the first 12 weeks, the last 
12 weeks, and the 24 weeks of the Maintenance Phase. 
Time on ESL will be calculated from the first dose to the last known dose of ESL. The median 
time and 95% CI will be estimated using Kaplan Meier time to event methods. Subjects who 
were still on ESL at the end of study will be censored at the end of study. Subjects who dropped 
out of the study while receiving treatment will be an event at the time of the dropout. Change in 
dosage levels during the treatment period will be ignored. 
15.3.7. 
Other Analyses 
15.3.7.1. Neurological Disorders Depression Inventory for Epilepsy Score 
The NDDI-E score and change from baseline for each evaluation time point will be summarized 
descriptively. 
15.3.7.2.  Profile of Mood States Short-form Score 
The POMS-SF scores and changes from baseline for each evaluation time point will be 
summarized descriptively. 
15.3.7.3.  Mood States Short-form Score 
The MOAS scores and changes from baseline for each evaluation time point will be summarized 
descriptively. 
15.3.7.4.  Quality of Life in Epilepsy-Patient-Weighted Score 
The QOLIE-31-P scores and changes from baseline for each evaluation time point will be 
summarized descriptively. 
15.3.7.4.1. EuroQol Five Dimensions Questionnaire Score 
The EQ-5D scores and changes from baseline for each evaluation time point will be summarized 
descriptively. 
15.3.7.5.  Clinical Global Impression of Improvement Score 
The CGI-I score for each evaluation time point will be summarized descriptively. 
15.3.7.6.  Patient’s Global Impression of Change Score 
The PGI-C score for each evaluation time point will be summarized descriptively. 


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15.3.8. 
Safety Analyses 
15.3.8.1. Adverse Events 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
version 13.1 or higher. AEs are untoward medical occurrences: 
 that occurred on or after the first dose of study medication. 
 with a missing start date and a stop date on or after the first dose of study medication, 
OR 
 with both a missing start and stop date. 
AEs will be summarized by MedDRA system organ class (SOC) and Preferred Term (PT). 
The following AEs will be summarized and presented by MedDRA SOC and PT for the Safety 
population: 
 All AEs (including number of events and subject incidence). 
 AEs by severity (mild, moderate, severe). 
 AEs by relationship to the study treatment (related, or not related). 
The following conventions will be followed in summarizing AEs: 
 For subject incidence summaries, each subject will be counted only once within each 
SOC and within each PT. 
 If a subject reports more than one AE within a PT and/or a SOC, the AE with the 
highest known severity within each SOC and within each PT will be included in the 
summaries by severity. 
 For summaries by relationship to the study medication, AEs will be grouped as 
“related” or “not related.” AEs assessed as “possible,” “probable,” or “definite,” will 
be grouped as “related.” If a subject reports more than one AE SOC and PT, and any 
are related, it will be summarized as related. 
Summaries of SAEs, AEs leading to discontinuation or other AE summaries will also be 
provided if necessary. A listing of AEs, as well as a listing of deaths, SAEs, and AEs leading to 
discontinuation, will be presented. 
15.3.8.2. Adverse Event Profile 
The individual LAEP scores and changes from baseline for each evaluation time point will be 
summarized for each symptom descriptively. The total score and change from baseline will be 
also summarized. A listing of LAEP will be provided. 
15.3.8.3. Clinical Laboratory Assessments 
For laboratory parameters with continuous outcomes, descriptive statistics (number of subjects, 
mean, standard deviation, median, minimum, and maximum) will be presented. For laboratory 
parameters with categorical outcomes, the number and percentage of subjects with each outcome 
will be presented. The number and percentage of subjects with potentially clinically significant 


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laboratory values will be summarized. The data listings for laboratory parameters will flag values 
outside of the reference range. Out of reference range findings with codes for clinical 
significance will be displayed in a separate data listing. Clinical laboratory variables will be 
summarized descriptively on the actual values and changes from baseline. Shift tables from 
baseline to the end of this study will be provided for laboratory parameters. 
15.3.8.4. Blood Sodium Levels 
In addition to descriptive summaries of blood sodium levels and changes from baseline for each 
assessment time point, the percent of subjects with normal baseline sodium level reaching 
≤ 135 mEq/L but > 130 mEq/L, ≤ 130 mEq/L but > 125 mEq/L, ≤ 125 mEq/L, and > 10 mEq/L 
reduction (ie, < -10 mEq/L) from baseline will be summarized by time point. 
15.3.8.5. Electrocardiograms 
ECG abnormalities will be presented in a data listing. 
15.3.8.6. Vital Signs and Weight 
Vital signs (supine systolic and diastolic blood pressures, respiratory rate, pulse rate, and oral 
temperature) and weight will be summarized using descriptive statistics at baseline and each 
evaluation visit. Change from baseline will be included in this presentation as well. In addition, a 
subject incidence (and percentage) of potentially clinically significant vital signs values will be 
presented. 
15.3.8.7. Physical/Neurological Examination 
All physical and neurological exam findings at screening will be captured in the medical history 
and summarized together with the other medical history events. Clinically significant changes 
from the screening visit will be captured as AEs as appropriate, and summarized together with 
the other AEs.  
15.3.8.8. Concomitant Medications 
All medications will be coded using the WHO-DRUG. 
Any medications taken during the course of the study, with a start date on or after the date of the 
first dose of study drug and on or before the date of the last dose of study drug; or with a start 
date prior to, and an end date on or after, the date of the first dose of study drug, or marked as 
ongoing, will be considered concomitant medications. Medications that ended prior to the date of 
the first dose of the study drug will be considered prior medications. The number and percentage 
of subjects using each concomitant medication will be summarized overall according to the 
WHO-DRUG Anatomic Therapeutic Chemical (ATC) level and PT. Subjects with multiple uses 
of a concomitant medication will be counted once by the ATC level and PT. 
15.3.8.9. Electronic Columbia-Suicide Severity Rating Scale 
The percentage of subjects in each classification class for overall and at each assessment time 
will be summarized. 


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15.3.9. 
Exploratory Analyses 
The proportions of concordance in the daily seizure frequency during the 24-weeks of the 
Maintenance Phase between the watch device and paper diary as well as between the Mate 
application and paper diary for each subject will be calculated.  
SSF during the first 12 weeks, the last 12 weeks, and the 24 weeks of the Maintenance Phase will 
be calculated using the seizure data recorded by the investigational wearable watch device, and 
MATE application from Empatica. The concordance correlation coefficient (CCC) with 95% 
confidence interval will be calculated to assess agreement in SSF during the first 12 weeks, the 
last 12 weeks, and the 24 weeks of the Maintenance Phase between the two Empatica devices 
and the paper diary. 
Scatter plots of the above SSFs using the seizure data recorded by the watch device as well as 
Mate application by those from the paper diary will be presented to evaluate agreement 
graphically. 
15.3.10. 
Treatment of Missing Data 
Subjects who dropped out before study completion are not to be replaced and all available 
information obtained from them will be included in the appropriate efficacy and safety 
summaries to the time of dropout. No imputation is planned for any safety measures. 
If the date of the seizure is missing or incomplete and the seizure cannot be allocated to a study 
period, these data will not be used in the analysis, but will be presented in the subject data 
listings. If the seizure diary was returned and there was no seizure data available for a particular 
day during that evaluation period, it will be assumed that the patient had missing seizure data, 
and the day will be excluded from the calculation of the standardized seizure frequency. 
Seizure-related variables will be calculated based on available data. For dropout subjects, their 
seizure frequency will be derived up to the last period where the subject had data. The last period 
SSF will be computed based on available data prior to dropout. 
 


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16. 
PROCEDURE FOR CLINICAL STUDY QUALITY CONTROL, 
DATA COLLECTION, MANAGEMENT, AND QUALITY 
ASSURANCE 
16.1. 
Data Collection/Electronic Data Capture 
The results from screening and data collected during the study (except clinical laboratory test 
results) will be recorded via electronic source data collection. The study centers will use an 
electronic system to record subject data. 
This protocol shall incorporate technology to capture source documents and source data 
electronically consistent with FDA Guidance for Industry “Computerized Systems Used in 
Clinical Investigations” (May 2007) and FDA Guidance for Industry “Electronic Source Data in 
Clinical Investigations” (September 2013). All electronic source documentation and data 
collected in this study shall “meet the same fundamental elements of data quality (e.g. 
attributable, legible, contemporaneous, original, and accurate) that are expected of paper 
records.” 
Sites will use a tablet PC to directly record subject data and clinical observations on electronic 
forms with a similar look/feel/behavior as paper forms. This permits the collection of both 
structured and unstructured information including ad-hoc comments, drawings, and relevant 
clinical notes the investigative site deems important. Information to be originally captured and 
reviewed electronically shall include but not limited to the details of the subject visit, Medical 
History, Adverse Events, and Concomitant Medications. The eSource technology platform 
possesses the ability to immediately validate data, highlight required and dependent data fields, 
as well as to document discrepancies at the time the data is originally captured. Because this 
study is using an electronic source record as the original point of data capture, there is no 
additional data entry step for the site – rather, the electronic source record directly populates the 
study database. 
16.2. 
Study Monitoring 
This study will be monitored from initiation to completion by the Sponsor or its representative. 
Monitoring will include personal visits and telephone communication to assure that the 
investigation is conducted according to protocol and in order to comply with ICH GCP. 
16.3. 
Audits 
The study may be subject to audit by the Sponsor/designee. If such an audit occurs, the 
Investigator must agree to allow access to required subject records. This is dependent on the 
subject granting consent by signing the ICF. By signing this protocol, the Investigator grants 
permission to personnel from the Sponsor or its representatives for on-site monitoring and 
auditing of all appropriate study documentation. 


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16.4. 
Study Documentation 
Study records are comprised of source documents and all other administrative documents, eg, 
IRB/IEC correspondence, clinical study materials and supplies shipment manifests, monitoring 
logs, Sponsor and CRO correspondence, etc. A study-specific binder will be provided with 
instructions for the maintenance of study records. 
Source document is defined as any hand written or computer generated document that contains 
medical information or test results that have been collected for or are in support of the protocol 
specifications, eg, clinical laboratory reports, clinic notes, drug disbursement log, subject sign in 
sheets, subject completed questionnaires if applicable, telephone logs, ECGs, etc. All draft, 
preliminary and pre-final iterations of a final report are also considered to be source documents, 
eg, faxed laboratory reports and hard copy laboratory reports, faxed initial results and hard copy 
final report. 
16.5. 
Clinical Laboratory Certification and Normal Values 
A central laboratory will be used for analysis for most of the clinical laboratory tests for this 
study. The central laboratory will provide the Investigator and Sponsor/CRO with laboratory 
certification(s) and a dated copy of normal range values for the central clinical laboratory 
selected to analyze clinical specimens. If an exception is granted to use a local laboratory, the 
Investigator must supply the Sponsor/CRO with laboratory certification, lab director’s curricula 
vitae and a current, dated copy of normal range values. 


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17. 
ETHICAL AND REGULATORY OBLIGATIONS 
17.1. 
Study Conduct 
The Investigator agrees that the study will be conducted according to the protocol, ICH GCP, 
ICH guidelines and the ethical principles that have their origin in the Declaration of Helsinki. 
The Investigator will conduct all aspects of the study in accordance with applicable local law(s) 
and regulation(s). 
The Investigator will assure proper implementation and conduct of the study including those 
study-related duties delegated to other appropriately qualified individuals. The Investigator will 
assure that study staff cooperate with monitoring and audits. 
The Investigator must sign and return to Sponsor/CRO the “Investigator Approval” page. 
The Investigator must provide a copy of current curriculum vitae (including a copy of a current 
medical license), and financial disclosure information. 
The Investigator must sign and return a completed Form Food and Drug Administration 
(FDA) 1572 “Statement of Investigator” to Sponsor/CRO. 
17.2. 
Institutional Review Board/Independent Ethics Committee 
Documented approval for conducting the study from appropriate IRB/IEC will be obtained for 
all participating study centers prior to initiation of the study, according to ICH GCP, applicable 
local law(s) and regulation(s). When necessary, an extension, amendment or renewal of the 
IRB/IEC approval must be obtained and also forwarded to the Sponsor. The IRB/IEC must 
supply the Sponsor a list of the IRB/IEC membership, and a statement to confirm that the 
IRB/IEC is organized and operates according to ICH GCP, applicable law(s) and regulation(s). 
A copy of written IRB/IEC approval or favorable opinion of the protocol, ICF and subject 
recruitment material (if applicable) must be provided to Sponsor/CRO prior to start of the study. 
The approval or favorable opinion letter must be signed by the IRB/IEC chairman or designee, 
identify the IRB/IEC name and address, identify the clinical protocol by title and/or protocol 
number, and include the date that approval or favorable opinion was granted. The letter must also 
contain a statement that the IRB/IEC complies with the requirements in 21 Code of Federal 
Regulations (CFR) Part 56 for a study conducted under a US IND or ICH GCP, as applicable. 
The Investigator/CRO is responsible for obtaining from the IRB/IEC continued review of the 
clinical research or submitting periodic progress reports, in accordance with applicable 
regulations, at intervals not to exceed one year and (if applicable) as otherwise additionally 
specified by the IRB/IEC. The Sponsor must be supplied with written documentation of 
continued review of the clinical research. 
The Investigator must promptly inform their IRB/IEC of all SAEs reported by subjects enrolled 
in the study or other safety information reported from Sponsor/CRO in accordance with 
applicable law(s) and regulation(s). 


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17.3. 
Informed Consent 
The ICFs (the ICF provided to all subjects as well as the ICF provided to subjects providing 
samples for genetic testing) will be approved by the Sponsor/CRO prior to submission to the 
IRB/IEC. The CRO may provide a template ICF to be qualified by each research facility to 
conform to local requirements. All ICFs must contain the minimum elements as mandated by 
ICH GCP, applicable local law(s) and regulations and will be subject to Sponsor/CRO approval 
as well as IRB/IEC approval. 
Before recruitment and enrollment, each prospective subject will be given a full explanation of 
the study, allowed to read the approved ICF and be provided ample time and the opportunity to 
ask any questions that may arise. Once all questions have been answered and the Investigator is 
assured that the prospective subject understands the implications of participating in the study, the 
prospective subject will be asked to give consent to participate in the study by signing the ICF. 
As part of the consent process, each prospective subject must consent to direct access to his/her 
medical records for study-related monitoring, auditing, IRB/IEC review, and regulatory 
inspection. It should be clearly explained to each prospective subject that participation in each 
and every clinical visit and assessment is expected. The Investigator will provide a copy of the 
signed ICF to each subject, and will record the date of the informed consent on the CRF. 
If an amendment to the protocol changes the subject participation schedule in scope or activity, 
or if important new information becomes available that may be relevant to the subject’s consent, 
the ICF must be revised, submitted to the IRB/IEC for review and approval or favorable opinion. 
The revised ICF must be used to obtain consent from a subject currently enrolled in the study if 
he or she is affected by the amendment. The revised ICF must be used to obtain consent from 
any new subjects who are enrolled into the study after the date of the approval or favorable 
opinion of the protocol amendment. 
17.4. 
Subject Privacy 
The Sponsor (or Sponsor representative) or any designees affirm to uphold the subjects 
confidentiality. The subject will be identified by unique code only; full names will be masked 
prior to transmission to the Sponsor. The confidentiality of the subject’s personal data shall be 
protected in accordance with appropriate laws and regulations. 
17.5. 
Protocol Amendments and Emergency Deviations 
All revisions and/or amendments to this protocol must be approved in writing by the Sponsor 
and the appropriate IRB/IEC. The Investigator will not make any changes to the conduct of the 
study or the protocol without first obtaining written approval from the Sponsor and the IRB/IEC, 
except where necessary to eliminate an apparent immediate hazard to a study subject. 
Emergency deviations or modifications may be initiated without Sponsor or IRB/IEC approval or 
favorable opinion, only in cases where the deviation or modification is necessary to eliminate or 
avoid an immediate apparent hazard to subjects. Emergency deviations or modifications must be 
reported to the Sponsor/CRO and the IRB/IEC immediately/within five business days of the 
occurrence, or in accordance with applicable regulatory requirements. 


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17.6. 
Records Retention 
The Investigator/the study center must arrange for retention of study records at the study center 
for at least 15 years from time of participation in the study or longer in accordance with 
applicable regulations and Sponsor standard operating procedure. The Investigator/site should 
take measures to prevent accidental or premature destruction of these documents. Documents 
cannot be destroyed without written Sponsor authorization. The Sponsor will inform the 
Investigator/the study center when the destruction of documents is permitted. 
17.7. 
Inspection of Records 
In the event of an inspection, the Investigator agrees to allow representatives of the Sponsor and 
its representative and, the regulatory authorities’ access to all study records. The Investigator will 
promptly notify the Sponsor/CRO of all requests to inspect a Sunovion-sponsored study by 
government agencies and will promptly forward a copy of all such inspection reports. 
17.8. 
Financial Disclosure 
By signing this protocol, the Investigator agrees to provide to the Sponsor prior to start of study 
accurate financial information to allow the Sponsor to submit complete and accurate certification 
and disclosure statements as required by the US FDA regulations (21 CFR Part 54). The 
Investigator further agrees to provide this information on a Financial Disclosure/Certification 
Form that is provided by the Sponsor. The Investigator will update this information if there are 
any relevant changes during the conduct of the study and for one year after completion of the 
study. 
The Investigator also consents to the transmission of this information to the Sponsor for these 
purposes. This may involve the transmission of information to countries that do not have laws 
protecting personal data. 
17.9. 
Publication Policy 
Any formal presentation or publication of data collected as a direct or indirect result of the study 
will be considered a joint publication by the Investigators and the appropriate personnel of the 
Sponsor. For multicenter studies, it is mandatory that the first publication is based on all data 
obtained from all analyses as stipulated in the protocol. Investigators participating in multicenter 
studies must agree not to present data gathered individually or by a subgroup of centers before 
the full, initial publication, unless this has been agreed to by all other Investigators and by the 
Sponsor. 


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18. 
REFERENCES 
Commission on Classification and Terminology of the International League Against Epilepsy 
(ILAE). Proposal for revised clinical and electroencephalographic classification of epileptic 
seizures. Epilepsia 1981;22:489-501. 
Committee for Proprietary Medicinal Products (CPMP). Note for guidance on clinical 
investigation of medicinal products in the treatment of epileptic disorders. London, England; 
22 January 2009 (CHMP/EWP/566/98 Rev. 2). 
Dreifuss FE. Proposal for revised clinical and electroencephalographic classification of epileptic 
seizures. Epilepsia. 1981;22:249-60. 
Epilepsy Fact Sheet. World Health Organization (WHO), World Health Organization, Feb 2016 
[Accessed 17 Oct 2016]. http://www.who.int/mediacentre/factsheets/fs999/en/ 
FDA Guidance for Industry. Computerized Systems Used in Clinical Investigations, May 2007. 
Available at: http://www.fda.gov/OHRMS/DOCKETS/98fr/04d-0440-gdl0002.pdf. Accessed 
10 February 2017. 
FDA Guidance for Industry. Electronic Source Data in Clinical Investigations. September 2013. 
Available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/U
CM328691.pdf. Accessed 10 February 2017. 


Protocol SEP093-701, Version 3.01 
 
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16 November 2017 
19. 
INVESTIGATOR APPROVAL 
I have read the protocol, SEP093-701, “Efficacy and Safety of Eslicarbazepine Acetate as First 
Add-on to Levetiracetam or Lamotrigine Monotherapy or as Later Adjunctive Treatment for 
Subjects with Uncontrolled Partial-onset Seizures: A Multicenter, Open-label, Non-randomized 
Trial” Version 3.01, and agree that it contains all necessary details for conducting the study and 
to conduct the study in strict accordance with the specifications outlined herein. 
I agree that no additional procedure(s) will be added during the conduct of the study except 
through protocol amendment by Sunovion Pharmaceuticals Inc. and after documentation of IRB 
approval. 
Investigator Signature: ____________________________________________________ 
Print Investigator Name: __________________________________________________ 
Date: ___________________________________________ 
 
 


Protocol SEP093-701, Version 3.01 
 
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16 November 2017 
20. 
APPENDIX I. CLINICAL LABORATORY TESTS 
Clinical Safety Panel 
HEMATOLOGY: (Differential reported as % and absolute value) 
Hemoglobin, Hematocrit, Platelet Count, Red Blood Cell Count, WBC - Total Count, WBC 
Differential, (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils) 
BLOOD CHEMISTRIES: Alanine aminotransferase (ALT), Alkaline Phosphatase (ALP), 
Aspartate aminotransferase (AST), Bicarbonate (HCO3), Bilirubin (Total, Direct, Indirect), 
Blood Urea Nitrogen (BUN), Calcium (Ca), Chloride (Cl), Creatinine, Glucose, Magnesium 
(Mg), Phosphorus (P), Potassium (K), Protein (Total), Sodium (Na), Uric Acid, Albumin 
URINALYSIS: Blood, Glucose, Ketones, Leukocyte esterase, Microscopic examination, 
Nitrites, pH, Protein 
THYROID PANEL: Free T3, Free T4, TSH 
RENAL FUNCTIONING: Creatinine clearance (calculated glomerular filtration rate using the 
Cockcroft-Gault equation) at Screening only. 
URINE DRUG SCREENING: Amphetamines, Barbiturates, Benzodiazepines, Cocaine, 
Methamphetamines, Methadone, Methylenedioxymethamphetamine (MDMA), Phencyclidine 
(PCP), Opiates, Oxycodone 
OTHER TESTS: Serum Pregnancy (-hCG) in female subjects of childbearing potential, only; 
Urine Pregnancy Test (in female subjects of childbearing potential only, on-site testing) 
Laboratory reports will be initialed and dated on all pages by the Investigator listed on the Form 
FDA 1572 (MD or DO). Laboratory test results will be reviewed by the Investigator as they 
become available. The Investigator must determine the clinical significance of all out-of-range 
lab values (except drug screens). Possibly drug-related or clinically relevant abnormal values of 
uncertain causality must be repeated. Any abnormal values that persist should be followed at the 
discretion of the Investigator. 


Protocol SEP093-701, Version 3.01 
 
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21. 
APPENDIX II. CARDIAC SAFETY MONITORING  
1. Requirements for Testing 
Electrocardiogram equipment and supplies will be provided by the site.  
 All 12-lead ECGs will be recorded in the same manner. 
 The study center personnel must be adequately trained in performing ECGs.  
 To the extent possible, the same ECG machine and personnel should be used to 
acquire a subject’s ECGs throughout the period of their participation in the study. 
 ECGs will be recorded with at least one 10-second single-lead tracing recorded from 
Lead II. 
2. Subject Restrictions and Instructions 
 Prior to ECG acquisition, the subject will have rested 10 minutes in the supine 
position and will remain so until the ECG is obtained. 
3. Reporting 
 It is the responsibility of the Investigator to perform a safety review of the ECG data 
for changes from previous assessments and/or emergent cardiac dysfunction, and to 
determine subjects’ eligibility or continuance in the study. Abnormalities require 
comment such as “not clinically significant” or “clinically significant.” Typically, 
clinically significant events will be reported as adverse events. 
 ECGs will be reviewed, signed and dated by the Investigator listed on the Form 
FDA 1572 (MD or DO) after each ECG collection. The same Investigator should 
review all ECG reports for a given subject whenever possible. 
 The ECG tracing will be kept with subject’s source documentation and/or CRF unless 
it is specified otherwise. The original ECG will be retained at the study center and the 
Sponsor may collect a copy. 


Protocol SEP093-701, Version 3.01 
 
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16 November 2017 
22. 
APPENDIX III. SAMPLE DAILY SEIZURE DIARY 
Subjects (or their caregiver) will be required to complete a daily seizure diary, regardless 
whether a seizure has occurred for a given day. A daily seizure diary will be provided to 
subjects/caregivers (sample provided below).


Protocol SEP093-701, Version 3.01 
 
Eslicarbazepine acetate 
Confidential and Proprietary 
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16 November 2017 
 
 
Protocol: SEP093-701 
Subject #: 
______-______ 
Subject Initials: 
____-____-____ 
 
Seizure Code 
Seizure Type 
Seizure Description 
(to be completed by PI with the patient/caregiver) 
A 
Simple partial 
 
B 
Complex partial 
 
C 
Partial with Secondary 
Generalization 
 
D 
Other 
 
 
 
 
 


Protocol SEP093-701, Version 3.01 
 
Eslicarbazepine acetate 
Confidential and Proprietary 
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16 November 2017 
 
Protocol: SEP093-701 
Subject #: 
______-______ 
Subject Initials: 
____-____-____ 
 
Daily Seizure Record 
DATE 
(DD/MMM/YYYY) 
SEIZURES 
Did I have 
any seizures 
today? 
Seizure code with 
# of Seizures (per code) 
_ _  / _ _ _ / _ _ _ _ 
Yes 
No 
A 
B 
C 
D 
 
 
 
 
_ _  / _ _ _ / _ _ _ _ 
Yes 
No 
A 
B 
C 
D 
 
 
 
 
_ _  / _ _ _ / _ _ _ _ 
Yes 
No 
A 
B 
C 
D 
 
 
 
 
_ _  / _ _ _ / _ _ _ _ 
Yes 
No 
A 
B 
C 
D 
 
 
 
 
_ _  / _ _ _ / _ _ _ _ 
Yes 
No 
A 
B 
C 
D 
 
 
 
 
 

SAP_001.pdf: 
 
Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN 
 
PROTOCOL SEP093-701 
 
Efficacy and Safety of Eslicarbazepine Acetate as First Add-on to Levetiracetam or 
Lamotrigine Monotherapy or as Later Adjunctive Treatment for Subjects with 
Uncontrolled Partial-onset Seizures: A Multicenter, Open-label, Non-randomized Trial 
 
 
 
Version Number and Date: Final, 09-JUL-2019 
 
 
 


 
Statistical Analysis Plan 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE - AUTHOR 
 
 
Name 
Signature 
Date 
Author: 
 
 
 
 
Position: 
 
 
Company: 
 
 
 
 


 
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STATISTICAL ANALYSIS PLAN SIGNATURE PAGE - APPROVAL 
Upon review of this document, the undersigned approves this version of the Statistical 
Analysis Plan, authorizing that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date 
Approved By: 
 
 
 
        Position: 
 
       Company: 
 
 
Approved By: 
 
 
 
        Position: 
 
       Company: 
 
 
Approved By: 
 
 
 
        Position: 
 
       Company: 
 
 
 
 
 
Approved By: 
 
 
 
        Position: 
 
       Company: 
 


 
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 MODIFICATION HISTORY 
 
Unique 
Identifier for this 
Version 
Date of the 
Document 
Version 
Author 
Significant Changes from  
Previous Authorized Version 
1.0 
28SEP2018 
 
Not Applicable – First Version 
2.0 
22OCT2018 
 
Update based on Sunovion comments 
Final Draft 
11JUN2019 
 
Update based on Sunovion comments 
Final 
09JUL2019 
 
Update based on Sunovion comments 
 
 
 


 
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TABLE OF CONTENTS 
1.  INTRODUCTION 
14 
2.  STUDY OBJECTIVES 14 
2.1. 
Primary Objective 
14 
2.2. 
Secondary Objectives 
14 
2.3. 
Exploratory Objectives 
14 
2.4. 
Study Endpoints 
15 
 
Primary Endpoint 
15 
 
Secondary Efficacy Endpoints 
15 
 
Other Efficacy Endpoints 
16 
 
Safety Endpoints 
16 
 
Exploratory Endpoints 
17 
3.  STUDY DESIGN 17 
3.1. 
General Description 
17 
3.2. 
IXRS and Dispensing of Study Drugs 
18 
3.3. 
Determination of Sample Size 
18 
3.4. 
Changes in the Conduct of the Study or Planned Analyses 
19 
 
Change in the Conduct of the Study 
19 


 
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Changes from Analyses Planned in the Protocol 
19 
3.5. 
Schedule of Assessments 
20 
4.  PLANNED ANALYSES 
26 
4.1. 
Data Monitoring Committee (DMC) 
26 
4.2. 
Interim Analysis 
26 
4.3. 
Final Analysis 
26 
5.  ANALYSIS POPULATIONS 26 
5.1. 
Safety Population 
26 
5.2. 
Modified Intent‐to‐Treat [mITT] Population 
26 
5.3. 
Per Protocol [PP] Population 
27 
6.  GENERAL CONSIDERATIONS 
27 
6.1. 
General Principles 
27 
6.2. 
Reference Start Date and Study Day 
27 
6.3. 
Baseline 
28 
6.4. 
Retests, Unscheduled Visits and Early Discontinuation Visit (EDV) 
28 
6.5. 
Windowing Conventions 
29 
6.6. 
Statistical Tests 
29 
6.7. 
Common Calculations 
29 


 
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6.8. 
Software Version 
29 
7.  STATISTICAL CONSIDERATIONS 29 
7.1. 
Multicenter Studies 
29 
7.2. 
Handling of Dropouts or Missing data 
30 
7.3. 
Multiple Comparisons/Multiplicity 
30 
7.4. 
Examination of Subgroups 
30 
8.  OUTPUT PRESENTATIONS 32 
9.  DISPOSITION AND WITHDRAWALS 
32 
10.  IMPORTANT PROTOCOL DEVIATIONS 32 
11.  DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
33 
11.1. 
Derivations 
33 
12.  MEDICAL AND EPILEPSY HISTORY 
34 
12.1. 
Medical History 
34 
12.2. 
Epilepsy History 
34 
13.  PRIOR AND CONCOMITANT MEDICATIONS 
34 
14.  STUDY MEDICATION EXPOSURE 35 
14.1. 
Derivations 
36 


 
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15.  OUTCOMES VARIABLES 
36 
15.1. 
Primary Variable 
36 
 
Primary Variable & Derivation(s) 
36 
 
Primary Analysis of Primary Outcome Variable 
37 
15.2. 
Efficacy Variables 
37 
 
Efficacy Variables and Derivation 
37 
15.2.1.2. 
Relative Reduction in SSF 
38 
15.2.1.3. 
Responder Rates 
39 
15.2.1.4. 
Proportion of Seizure‐Free Subjects 
39 
15.2.1.5. 
Time on ESL 
39 
 
Analysis of Efficacy Variables 
40 
15.2.2.2. 
Standard Seizure Frequency (SSF) 
40 
15.2.2.3. 
Responder Rates 
40 
15.2.2.4. 
Relative Reduction in SSF 
40 
15.2.2.5. 
Proportion of Seizure‐Free Subjects 
41 
15.2.2.6. 
Time on ESL 
41 
15.3. 
Subgroup Analysis of Efficacy Variable(s) 
41 
15.4. 
Exploratory Variables 
41 
 
Analysis of Exploratory Variables 
41 
15.5. 
Quality of Life Analysis 
43 


 
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Variables & Derivations 
43 
15.5.1.1. EuroQol Five Dimensions Questionnaire (EQ‐5D) scores 
43 
15.5.1.2. Clinical Global Impression (CGI) – Improvement 
45 
15.5.1.3. Patient Global Impression of Change (PGIC) 
45 
15.5.1.4 
. Quality of Life in Epilepsy‐Patient‐Weighted (QOLIE‐31‐P) 
45 
15.5.1.5. 
Profile of Mood States Short‐form (POMS‐SF) 
49 
15.5.1.6. 
Neurological Disorders Depression Inventory for Epilepsy (NDDI‐E) 
50 
15.5.1.7. 
Modified Overt Aggression Scale (MOAS) 
50 
 
Analysis of QOL Variables 
52 
15.5.2.2. 
Analysis of EuroQol Five Dimensions Questionnaire (EQ‐5D) 
52 
15.5.2.2. Analysis of Clinical Global Impression of Improvement (CGI‐I) 
53 
15.5.2.3 
. Analysis of Patient's Global Impression of Change (PGI‐C) 
53 
15.5.2.4. 
Analysis of Quality of Life in Epilepsy‐Patient‐Weighted (QOLIE‐31‐P) 
53 
15.5.2.5. 
Analysis of Profile of Mood States Short‐form (POMS‐SF) 
53 
15.5.2.6. 
Analysis of Neurological Disorders Depression Inventory (NDDI‐E) 
54 
15.5.2.7. 
Analysis of Modified Overt Aggression Scale (MOAS) 
54 
16.  SAFETY OUTCOMES 54 
16.1. 
Pre‐treatment and Adverse Events 
54 
 
All AEs 
55 
 
Severity 
55 


 
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Relationship to Study Medication 
56 
 
AEs Leading to Discontinuation of Study Medication 
56 
 
Serious Adverse Events 
56 
 
Non‐Serious Adverse Events 
57 
 
Adverse Events Leading to Death 
57 
16.2. 
Laboratory Evaluations 
57 
 
Blood Sodium Levels 
58 
 
Laboratory Reference Ranges and Potentially Clinically Significant (PCS) 
58 
16.3. 
ECG Evaluations 
59 
16.4. 
Vital Signs 
59 
16.5. 
Physical/Neurological Examination 
60 
16.6. 
Other Safety Assessments 
60 
 
Electronic Columbia Suicide Severity Rating Scale (eC‐SSRS) 
60 
 
Score of AED‐specific AEs (by the Liverpool Adverse Event Profile [LAEP]). 
63 
17.  REFERENCES 65 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 66 
APPENDIX 2. PARTIAL DATE CONVENTIONS 
68 
APPENDIX 3.  PCS CRITERIA FOR LABORATORY PARAMETERS 
75 
 


 
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List of Abbreviations 
Abbreviation  Full Form  
AE  
Adverse event  
AED  
Anti-epileptic drugs  
ALT  
Alanine aminotransferase  
AST  
Aspartate aminotransferase  
CGI-I  
Clinical Global Impression of Improvement  
CI  
Confidence Interval  
C-SSRS  
Columbia-Suicide Severity Rating Scale  
ECG  
Electrocardiogram  
eC-SSRS  
Electronic Columbia-Suicide Severity Rating Scale  
EDV  
Early discontinuation visit  
EOS  
End of study  
EQ-5D  
EuroQol Five Dimensions Questionnaire  
ESL  
Eslicarbazepine acetate  
HLA  
Human leukocyte antigen  
ICF  
Informed consent form  
IPD  
Important protocol deviations  
IXRS  
Interactive Web/Voice Response System  
LAEP  
Liverpool Adverse Event Profile  
LEV  
Levetiracetam  
LTG  
Lamotrigine  
MedDRA  
Medical Dictionary for Regulatory Activities  
mITT  
Modified Intent-To-Treat  
med 
Medication 
MOAS  
Modified Overt Aggression Scale  
NDDI-E  
Neurological Disorders Depression Inventory for Epilepsy  
OXC  
Oxcarbazepine  
PCS 
Potentially Clinically Significant 
PGI-C  
Patient’s Global Impression of Change  


 
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PP 
Per Protocol 
POMS-SF  
Profile of Mood States Short-form  
POS  
Partial-onset seizures  
PT  
Preferred term  
QD  
Once daily  
QOL  
Quality of life  
QOLIE-31-P  
Quality of Life in Epilepsy-Patient-Weighted (31-item)  
SAE  
Serious adverse event  
SOC  
System organ class  
SSF  
Standard seizure frequency  
T3  
Triiodothyronine  
T4  
Thyroxine  
TSH  
Thyroid stimulating hormone  
WBC  
White blood cell  
WHO-DRUG  World Health Organization drug dictionary  
 
 


 
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1. Introduction 
This document describes the rules and conventions to be used in the presentation and analysis 
of efficacy and safety populations data for Protocol SEP093-701. It describes the data to be 
summarized and analyzed, including specifics of the statistical analyses to be performed.  
This statistical analysis plan (SAP) is based on protocol version 3.02 dated 04Oct 2018.  
2. Study Objectives 
2.1. Primary Objective 
The primary objective is to evaluate the effectiveness (measured by study retention rate) of ESL 
administered once daily (QD) as the first adjunctive therapy to levetiracetam (LEV) or 
lamotrigine (LTG) or as later adjunctive therapy in subjects with POS over a 24-week 
maintenance period in a real-world clinical setting. 
2.2. Secondary Objectives 
The secondary objectives are  
 To evaluate the efficacy of ESL QD as a first or later adjunctive therapy based on the 
number of seizures reported over a 24-week maintenance period. 
 To evaluate the safety and tolerability of ESL QD as a first or later adjunctive therapy. 
 To evaluate the effect of treatment with ESL QD on the quality of life (QOL), behavior, 
and mood. 
2.3.  Exploratory Objectives 
The exploratory objectives are 


 
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 To evaluate the accuracy of an investigational wearable watch device from Empatica in 
recording seizure counts. 
 To evaluate the performance of an investigational electronic seizure diary in the form of a 
smartphone application (Empatica MATE). 
2.4.  Study Endpoints 
 
Primary Endpoint 
The primary endpoint is the proportion of subjects completing 24 weeks adjunctive therapy 
during Maintenance Phase (Visit 9). 
 
Secondary Efficacy Endpoints 
 Seizure data via the paper diary will be used to calculate the following seizure related 
endpoints: 
o 
Standard Seizure Frequency (SSF) during the first 12 weeks, the last 12 weeks, and 
the 24 weeks of the Maintenance Phase. 
o 
50% and 75% responder rate (calculated as 50% and 75% reduction in SSF from 
baseline) as evaluated during the first 12 weeks, the last 12 weeks, and the 24 weeks 
of the Maintenance Phase. 
o 
Relative reduction (%) in SSF from baseline during the first 12 weeks, the last 12 
weeks, and the 24 weeks of the Maintenance Phase. 
o 
Proportion of seizure-free subjects during the first 12 weeks, the last 12 weeks, and 
the 24 weeks of the Maintenance Phase. 
 Time on ESL 


 
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Other Efficacy Endpoints 
 Changes from baseline in the Neurological Disorders Depression Inventory for Epilepsy 
(NDDI-E)-6-item questionnaire. 
 Changes from baseline in the Profile of Mood States Short-form (POMS-SF). 
 Changes from baseline in the agitation/behavioral measurements as evaluated by the 
Modified Overt Aggression Scale (MOAS). 
 Changes from baseline in Quality of Life in Epilepsy-Patient-Weighted (QOLIE-31-P) 
scores. 
 Change from baseline in EuroQol Five Dimensions Questionnaire (EQ-5D) scores. 
 Clinical Global Impression of Improvement (CGI-I) scores at each evaluation time point. 
 Patient’s Global Impression of Change (PGI-C) scores at each evaluation time point 
 
Safety Endpoints 
 Number and percentage of subjects with AEs. 
 Number and percentage of subjects with serious adverse events (SAEs). 
 Number and percentage of subjects with AEs leading to discontinuation. 
 Electronic Columbia-Suicide Severity Rating Scale (eC-SSRS): Proportion (%) of events 
in each classification class (as completed by the subject).  
 Changes from baseline in clinical laboratory parameters, including thyroid panel.  
 Changes from baseline in vital signs parameters.  
 Score of AED-specific AEs (by the Liverpool Adverse Event Profile [LAEP]).  


 
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Exploratory Endpoints 
 Seizure data recorded by an investigational wearable watch device from Empatica. 
 Seizure data recorded by an investigational electronic seizure diary from Empatica MATE 
application. 
3. Study Design 
3.1. General Description 
This is a 31-week, multicenter, 2-arm, prospective, open-label, non-randomized, Phase 4 study of 
ESL as adjunctive therapy in adult subjects with a diagnosis of epilepsy with POS. Two groups 
of ESL-naïve subjects will be evaluated. The groups are defined as follows: 
Arm 1 (ESL as first add-on): This group will include subjects who have been maintained on a 
regimen consisting of a stable dose of LEV or LTG for at least 1 month (28 days) prior to 
screening and who have not used any adjunctive treatment. 
Arm 2 (ESL as later add-on): This group will include subjects who have been maintained on a 
regimen consisting of a stable dose of 1 - 2 anti-epileptic drugs (AEDs) (excluding oxcarbazepine 
[OXC]) for at least 1 month (28 days) prior to screening and who have used adjunctive treatment 
in the past. 
The Arm 1 subjects will allow an assessment of the efficacy and safety of ESL in subjects who 
are early in the course of their disease and being treated with one of the most common first line 
AEDs. The subjects in Arm 2 are similar to the subject population in the Phase 3 adjunctive 
studies, treatment-resistant subjects who are later in the course of their disease. The inclusion of 
these subjects in the present study will provide an assessment of the efficacy and safety of ESL as 
a later adjunctive therapy in a real world clinical setting. In addition, this study will provide data 
from both Arm 1 and Arm 2 for several behavioral, mood-related, and QOL-related assessments 
that were not evaluated in in the Phase 3 program. 


 
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Approximately 100 subjects will be enrolled (approximately 50 subjects in Arm 1 and 50 subjects 
in Arm 2). 
The study will consist of a Screening Phase of 1 to 2 weeks, followed by a 2-week Titration 
Phase, a 24-week Maintenance Phase, and a Safety Follow-up/Taper Phase of 4 weeks. The last 
visit in the Maintenance Phase (Visit 9) is considered the End of Study (EOS) visit. 
The screening visit should take place 7 - 10 days prior to the titration visit and may be extended 
to 7 - 17 days if required with consent of medical monitor. Subjects of Asian ancestry who 
require HLA-B*1502 testing (eg do not have prior test results) may have the screening visit 7 - 
17 days prior to the titration visit. 
Subjects who withdraw prior to the EOS visit should have an Early Discontinuation Visit (EDV) 
within 72 hours. 
3.2. IXRS and Dispensing of Study Drugs 
An Interactive Web/Voice Response System (IXRS) will be used to register the Screening Visit 
(Visit 1) and assignment of the Subject Screening number. If the Subject is enrolled in the study 
the Screening number becomes the Subject number. The IXRS will also be utilized to register the 
Titration Visit (Visit 2), Maintenance Phase Visits (Visit 3 – Visit 9) and EDV. Study drug will 
be dispensed based on assignment by the IXRS at Visits 2 – Visit 8. At Visit 9 and EDV the 
IXRS will give an option to dispense an additional bottle of study drug if needed for taper. Please 
ensure to dispense the correct lot number(s) assigned to each Subject. In addition, the IXRS will 
be utilized to register Screen Failure and Acknowledgment of study drug receipt at site. 
3.3. Determination of Sample Size 
Sample size is determined outside of statistical consideration. Approximately 100 subjects will be 
enrolled, almost evenly split between Arm 1 (first add-on) and Arm 2 (later add-on). Assuming 
the completion rates at 24 weeks of the Maintenance Phase are 60% and 50% for Arm 1 and Arm 
2 respectively, the width of 95% CI for completion rate will be approximately 14% based on 
normal approximation method.  


 
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3.4. Changes in the Conduct of the Study or Planned Analyses 
 
Change in the Conduct of the Study 
Four amendments have been incorporated into protocol since final protocol. 
 
 Changes from Analyses Planned in the Protocol 
Since the study drug accountability data was not collected in the data source, the number of dose 
taken and average daily dose will not be calculated. 


 
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subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited 
3.5. Schedule of Assessments 
Study Period  
Screening  
Titrationa  
24-Week Maintenance Phasea 
EDVa  
Safety 
Follow-up  
Visit  
V1  
V2  
V3  
V4  
TC1  
V5  
V6  
TC2  
V7  
V8  
V9 (EOS)  
 
V10 or TC3  
Week  
-1 to  
-2o WKs  
WK 1  
Day 1  
WK 
 3  
WK 
 7  
WK 
 9  
WK 
 11  
WK  
15  
WK 
 17  
WK
 19  
WK
 23  
WK 27  
 
WK 31  
Windows (days)  
(+3)  
-  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
 
 ±7 
Procedures  
 
 
 
 
 
 
 
 
 
 
 
 
 
Informed Consent Form  
X  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
Genetic Consent for HLA-
B*1502 Characterization: 
Subjects of Asian Ancestry 
onlyb,o  
X  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
Genetic Consent for HLA 
genotyping (optional)c  
X  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
Review of Inclusion/ 
Exclusion Criteria  
X  
X  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
 


 
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subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited 
Study Period  
Screening  
Titrationa  
24-Week Maintenance Phasea 
EDVa  
Safety 
Follow-up  
Visit  
V1  
V2  
V3  
V4  
TC1 
V5  
V6  
TC2  
V7  
V8  
V9 (EOS)  
 
V10 or 
TC3  
Week  
-1 to -2o  
WKs  
WK 1  
Day 1  
WK 
 3  
WK 
 7  
WK 
9  
WK 
11  
WK 
 15  
WK 
17  
WK 
 19  
WK 
 23  
WK 27  
 
WK 31  
Windows (days)  
(+3)  
-  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
 
 ±7 
Procedures  
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics  
X  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
 
Medical and Neurologic 
History  
X  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
Complete DISCOVER form  
X  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
Administer HEP and Collect 
Seizure History Datad  
X  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
Prior/Concomitant 
Medicationse  
X  
X  
X  
X  
-  
X  
X  
-  
X  
X  
X  
X  
X  
Physical/Neurologic 
Examination  
X  
-  
X  
X  
-  
X  
X  
-  
-  
X  
X  
X  
-  
Vital Signs  
X  
X  
X  
X  
-  
X  
X  
-  
X  
X  
X  
X  
-  
Body Weight  
X  
X  
X  
X  
-  
X  
X  
-  
X  
X  
X  
X  
-  
Height  
X  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
12-lead ECG  
X  
-  
-  
-  
-  
-  
-  
-  
-  
-  
X  
X  
-  
Clinical Laboratory Testsf 
X 
 
 
 
 
 
 
 
 
 
X 
X 
 
  
 


 
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subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Period  
Screening  
Titrationa  
24-Week Maintenance Phasea 
EDVa  
Safety 
Follow-up  
Visit  
V1  
V2  
V3  
V4  
TC1  
V5  
V6  
TC2  
V7  
V8  
V9 (EOS)  
 
V10 or 
TC3  
Week  
-1 to  
-2o WKs  
WK 1  
Day 1  
WK  
3  
WK 
7  
WK 
9  
WK 
 11  
WK 
15  
WK 
17  
WK 
 19  
WK 
 23  
WK 27  
 
WK 31  
Windows (days)  
(+3)  
-  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
 
 ±7 
Thyroid panel (free 
T3, T4, and TSH)  
X  
-  
-  
-  
-  
-  
-  
-  
-  
-  
X  
X  
-  
Blood Sample for 
HLA-B*1502 testing: 
Subjects of Asian 
ancestry onlyg  
X  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
Genetic Saliva Sample 
and Questionnaire 
(optional)h  
-  
-  
-  
X  
-  
-  
-  
-  
-  
-  
-  
-  
-  
Serum β-hCGi  
X  
-  
-  
-  
-  
-  
-  
-  
-  
-  
X  
X  
-  
Urine Pregnancy Testi  
-  
X  
X  
X  
-  
X  
X  
-  
X  
X  
 
 
 
Urine Drug Screen  
X  
 
 
 
 
 
 
 
 
 
 
 
 
Liverpool Adverse 
Event Profilej  
-  
X  
X  
X  
-  
X  
X  
-  
X  
X  
X  
X  
-  
Adverse Events  
-  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 


 
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subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited 
Study Period  
Screening  Titrationa 
24-Week Maintenance Phasea 
EDVa 
Safety 
Follow-up  
Visit  
V1  
V2  
V3  
V4  
TC1 
V5  
V6  
TC2  
V7  
V8  
V9 (EOS) 
 
V10 or 
TC3  
Week  
-1 to -2o  
WKs  
WK 1  
Day 1  
WK 
 3  
WK 
7  
WK
 9  
WK 
11  
WK 
15  
WK  
17  
WK 
19  
WK  
23  
WK 27  
 
WK 31  
Windows (days)  
(+3)  
-  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
±3  
 
 ±7 
Procedures  
 
 
 
 
 
 
 
 
 
 
 
 
 
Pre-treatment 
Adverse Events  
X  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
Dispense Study 
Drug  
-  
X  
X  
X  
-  
X  
X  
-  
X  
X  
Xk  
Xp  
-  
Collect Study Drug  
-  
-  
X  
X  
-  
X  
X  
-  
X  
X  
X  
X  
-  
Record Any ESL 
Dose Change Since 
Last Visit  
-  
-  
X  
X  
X  
X  
X  
X  
X  
X  
X  
-  
-  
Record Any AED 
Dose Change Since 
Last Visit  
-  
-  
X  
X  
X  
X  
X  
X  
X  
X  
X  
X  
-  
Distribute Empatica 
Watchl  
X  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
 
 
 


 
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subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited 
Study Period  
Screening  
Titrationa  
24-Week Maintenance Phasea 
EDVa  
Safety 
Follow-up  
Visit  
V1  
V2  
V3  
V4  
TC1  
V5  
V6  
TC2  
V7  
V8  
V9 (EOS  
 
V10 or 
TC3  
Week  
-1 to -2o  
WKs  
WK 1  
Day 1  
WK 
 3  
WK 
7  
WK 
 9  
WK 
11  
WK 
15  
WK  
17  
WK 
19  
WK  
23  
WK 27  
 
WK 31  
Distribute Paper 
Seizure Diarym  
X  
X  
X  
X  
-  
X  
X  
-  
X  
X  
X  
X  
-  
Collect Paper Seizure 
Diary  
-  
X  
X  
X  
-  
X  
X  
-  
X  
X  
X  
X  
-  
Review Seizure 
Diaries  
 
X  
X  
X  
-  
X  
X  
-  
X  
X  
X  
X  
Xq 
EQ-5D  
-  
X  
-
-
-
X 
-
-
-  
-
X 
X 
-
CGI-I  
 
 
X 
-
-
X 
-
-
-  
-
X 
X 
-
PGI-C  
 
 
X 
-
-
X 
-
-
-  
-
X 
X 
-
QOLIE-31-P  
-  
X  
- 
- 
- 
X 
- 
- 
-  
- 
X 
X 
- 
POMS-SF  
-  
X  
- 
- 
- 
X 
- 
- 
-  
- 
X 
X 
- 
NDDI-E  
-  
X  
- 
- 
- 
X 
- 
- 
-  
- 
X 
X 
- 
MOAS  
-  
X  
-
-
-
X 
-
-
-  
-
X 
X 
-
eC-SSRSn  
X  
X  
X 
X 
-
X 
X 
-
X  
X 
X 
X 
-
Return of watch and 
data collection device  
-  
-  
-  
-  
-  
-  
-  
-  
-  
-  
X  
X  
-  
 
Abbreviations: AED = Antiepileptic drug; β-hCG = Beta-human chorionic gonadotropin; CGI-I – Clinical Global Impression of Improvement; CRF = case report form; eC-
SSRS = electronic Columbia-Suicide Severity Rating Scale; DISCOVER = Diagnostic Interview for Seizure Classification Outside of Video EEG Recording; ECG = 
Electrocardiogram; EDV = Early Discontinuation Visit; EOS = End of Study; EQ-5D = EuroQol Five Dimensions Questionnaire; ESL = Eslicarbazepine acetate; HEP = 
pre-Human Epilepsy Project; HLA = Human Leukocyte Antigen; MOAS = Modified Overt Aggression Scale; NDDI-E = Neurological Disorders Depression Inventory for 
Epilepsy; PGI-C = Patient’s Global Impression of Change; POMS-SF = Profile of Mood States Short-form; QOLIE-31-P = Quality of Life in Epilepsy-Patient-Weighted 
(31-item); T3 = Triiodothyronine; T4 = Thyroxine; TC = telephone call; TSH = Thyroid Stimulating Hormone; US = United States; WK = Week  


 
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a Eligible subjects will begin the 2-week Titration Phase on Day 1 (Week 1), during which they will initiate treatment with ESL at 400 mg/day and remain on that dose for 
1 week (Days 1 – 7). Subjects will titrate to ESL 800 mg/day the beginning of week 2 (Day 8) and will remain on that dose for 1 week up to the beginning of the 
maintenance phase. Subjects will maintain a minimum dose of 800 mg/day for the Maintenance Phase; however, during the Maintenance Phase, subjects may titrate in 
weekly increments of 400 mg/day as medically indicated at the discretion of the Investigator up to a maximum dose of 1200 mg/day (Canadian Sites) or 1600 mg/day (US 
sites), (based on maximum local labelled dose). Additional details are provided in Section 10.1.1. Subjects who withdraw prior to the (end of study) EOS visit should have 
an early discontinuation visit (EDV) within 72 hours.  
b Subjects of Asian ancestry (or subjects for whom the absence of Asian ancestry cannot be confirmed) who cannot provide documentation stating that they are not carriers 
of HLA-B*1502 must give written informed consent for genotyping. Asian ancestry will be based on subject self-report.  
c This consent for genetic saliva sample and associated questionnaire is optional.  
d Record seizure history (the number and types of seizures that occurred over the longest available period up to 3 months prior to screening).  
e Record all prior and concomitant medications, including over the counter medications, taken within the previous 60 days.  
f Includes clinical chemistry, hematology and urinalysis. Estimated creatinine clearance using Cockcroft-Gault equation at Screening only.  
g Required for subjects of Asian ancestry (or subjects for whom the absence of Asian ancestry cannot be confirmed) and who do not have documentation to show that they 
are not carriers of HLA-B*1502.  
h Subjects who provided optional separate informed consent/assent only.  
i A serum pregnancy test will be given to all female subjects of childbearing potential at screening. An on-site urine pregnancy test will be given to all female subjects of 
childbearing potential at Visits 1-8. Any positive urine pregnancy test will be followed up with a serum test for confirmation of pregnancy. A serum pregnancy test will be 
given to all females subjects of childbearing potential at Visit 9 (EOS) or at the EDV.  
j The Liverpool Adverse Event Profile collects information on AEs associated with AEDs.  
k Subjects who elect to continue on commercially available drug will not be dispensed additional ESL at this visit. Subjects who elect to discontinue ESL will be provided 
sufficient ESL to accommodate the appropriate taper regimen.  
l Subjects will be provided with the Empatica watch and instructed in the use of the watch.  
m Subjects will be provided a standardized paper daily seizure diary and an electronic daily seizure diary and instructed in the use of the diaries. Diaries are to be completed 
daily whether a seizure occurs or not.  
n The “Baseline/Screening” (lifetime) version should be administered at the screening visit and the “Since Last Visit” version at all other time points.  
o The screening visit should take place 7 - 10 days prior to the titration visit, and may be extended to 7 – 17 days if required with consent of medical monitor. Subjects of 
Asian ancestry who require HLA-B*1502 testing (eg, do not have prior test results) may have the screening visit 7 - 17 days prior to the titration visit.  
p Subjects who discontinue prior to the EOS visit will be provided sufficient ESL to accommodate the appropriate taper regimen.  
q At the Safety Follow-Up visit, the standardized paper daily seizure diary will not be collected; however it will be reviewed as part of the subject’s safety assessments.


 
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4. Planned Analyses 
The following analyses will be performed for this study: 
 Final Analysis  
4.1. Data Monitoring Committee (DMC)  
There will be no DMC for this study. 
4.2. Interim Analysis  
There will be no interim analysis for this study. 
4.3.  
Final Analysis  
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics 
following Sponsor Authorization of this Statistical Analysis Plan, Database Lock and Sponsor 
Authorization of Analysis Sets.  
5. Analysis Populations 
5.1.  
Safety Population   
The safety population will consist of all subjects who have taken any study medication. Safety 
population will be used for all analyses except efficacy analyses. 
5.2. Modified Intent-to-Treat [mITT] Population 
The modified intent-to-treat (mITT) population will include subjects who are in the safety 
population and have paper seizure data available. The mITT population will be used for efficacy 
analyses. 


 
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5.3.  Per Protocol [PP] Population 
The per protocol (PP) population will include subjects who are in the mITT population and did 
not have any important protocol deviations (IPDs). The per-protocol population will be used in 
an additional analysis of the efficacy endpoints and subject demographics and baseline 
characteristics. If no IPDs occurred, as determined by the review team before the database lock, 
analyses of PP population specified in the SAP will not performed. 
6. General Considerations 
6.1. General Principles 
Unless stated otherwise, all continuous variables, including those assessed on a discrete scale, 
will be summarized using descriptive statistics, including number of subjects, mean, standard 
deviation, minimum, 25th percentile, median, 75th percentile, and maximum. For categorical 
variables, summaries will include numbers of subjects and percentages. 
All endpoints will be summarized descriptively for Arm 1 and Arm 2 separately. There will be no 
statistical comparisons between Arm 1 and Arm 2. 
6.2. Reference Start Date and Study Day 
Study Day will be calculated from the reference start date and will be used to show start/ stop day 
of assessments and events.  
Reference start date is defined as the day of the first dose of study medication, (Day 1 is the day 
of the first dose of study medication) and will appear in every listing where an assessment date or 
event date appears.  
If the date of the event is on or after the reference date then:  
Study Day = (date of event – reference date) + 1 
If the date of the event is prior to the reference date then:  


 
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Study Day = (date of event – reference date) 
In the situation where the event date is partial or missing, Study Day, and any corresponding 
durations will appear partial or missing in the listings. 
6.3. Baseline 
For the seizure-related endpoints, baseline will be defined as the seizure data for the longest 
available period up to 3 months prior to screening from seizure history and from screening to first 
dose of study medication from the paper seizure diary. 
Hence, the period of baseline will be calculated as the days of (1 month, 2 months or 3 months) + 
the number of days from Screening to the first dose from paper seizure dairy.  One month will be 
calculated as 30.42 days. 
For all other endpoints, baseline will be defined as the last non-missing measurement taken prior 
to the first dose of study drug.  
6.4. Retests, Unscheduled Visits and Early Discontinuation Visit (EDV) 
In general, for by-visit summaries, data recorded at the nominal visit will be presented including 
visit 9 (EOS) and EDV. Unscheduled measurements collected prior to the first dose of study 
medication will contribute to the derivation of the baseline value.  
Unscheduled measurements collected post baseline will not be included in by-visit summaries but 
will contribute to the potentially clinically significant values for vital signs and labs and best/ 
worst case value where required (e.g. shift table). 
In the case of a retest (same visit number assigned), the latest available measurement for that visit 
will be used for by-visit summaries.  
Listings will include scheduled, unscheduled, retest and early discontinuation data. 


 
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6.5. Windowing Conventions 
No visit windowing will be performed for this study.  
Refer to Appendix 1 for the visit convention for this study. 
6.6. Statistical Tests 
There will be no statistical testing performed.  
6.7. Common Calculations 
For quantitative measurements, change from baseline will be calculated as: 
 
Test Value at Visit X – Baseline Value 
6.8. Software Version 
All analyses will be conducted using SAS version 9.4 or higher.  
7. Statistical Considerations 
As summaries are going to be descriptive in nature, there will not be any adjustments for 
covariates. 
7.1. Multicenter Studies 
This study will be conducted by multiple investigators at multiple centers with sites in the United 
States and Canada. There will be no summaries of data by site/pooled site or country. 


 
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7.2. Handling of Dropouts or Missing data 
Subjects who dropped out before study completion are not to be replaced and all available 
information obtained from them will be included in the appropriate efficacy and safety 
summaries to the time of dropout.  No imputation is planned for any safety measures. 
If the date of the seizure is missing or incomplete and the seizure cannot be allocated to a study 
interval, these data will not be used in the analysis, but will be presented in the subject data 
listings.  If the seizure diary was returned and there was no seizure data available for a day during 
that evaluation period, it will be assumed that the patient had missing seizure data, and the day 
will be excluded from the calculation of the standardized seizure frequency.   
Seizure related variables will be calculated based on available data.  For dropout subjects, their 
seizure frequency will be derived for each interval up to the last interval where the subject had 
data.  The last interval standardized seizure frequency (SSF) will be computed based on available 
data prior to dropout. 
7.3. Multiple Comparisons/Multiplicity 
There will be no multiple comparison/multiplicity for this study.  
7.4. Examination of Subgroups 
Subgroup analyses will be conducted as stated in the respective primary, efficacy and safety 
analysis sections. The following subgroups will be assessed. Determinations of the subgroups 
will be based on baseline data.  
Gender:  
o 
Female 
o 
Male 
Age Groups (years): 
o 
≥ 18 to <= 65  


 
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o 
 > 65  
Race Groups: 
o 
White 
o 
Black or African American  
o 
Asian 
o 
Other (American Indian/Alaska Native, Native Hawaiian or Other Pacific Islander, 
Multiple, Other) 
Baseline AEDs: 
 For Arm 1:  
o 
Use of lamotrigine as baseline AED (yes/no) 
o 
Use of levetiracetam as baseline AED (yes/no) 
 For Arm 2: 
o 
Use of lamotrigine as baseline AED (yes/no) 
o 
Use of levetiracetam as baseline AED (yes/no) 
o 
Use of carbamazepine as baseline AED (yes/no) 
o 
Use of valproic acid as baseline AED (yes/no) 
o 
Use of any other additional baseline AEDs that occur in >=15% of the subjects 
(yes/no) 
Number of Baseline AEDs: 
 For Arm 2: 
o 
1 
o 
2 
Seizure Type:  
o 
Simple Partial 
o 
Complex Partial 
o 
Partial Evolving to Secondarily Generalized Seizures 


 
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o 
Other 
8. Output Presentations 
Appendix 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describe the presentations for this study and therefore the 
format and content of the summary tables, figures and listings to be provided by IQVIA 
Biostatistics. 
9. Disposition and Withdrawals 
All subjects who provide informed consent will be accounted for in this study.  
Subject disposition will be summarized and presented for the number and percentage of subjects, 
who were screened, screen-failed, entered, completed the study, and discontinued early including 
reasons for discontinuations such as adverse event, lack of efficacy, withdrawal by subject, 
withdrawal by investigator, protocol deviation, study terminated by Sponsor, death, pregnancy 
and Other. 
Listing of subject disposition will also be provided.  
10. 
Important protocol deviations 
Prior to database lock, important protocol deviations (IPDs) will be identified in a review of all 
protocol deviations reported.  Possible IPDs will include, but may not be limited to, subjects who:  
• 
Did not meet inclusion/exclusion criteria or eligibility was not adequately verified  
• 
Received any disallowed concomitant medication  
• 
Developed withdrawal criteria but were not withdrawn  


 
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 Individual IPDs will be presented in a data listing.  The number and percentage of subjects with 
IPDs will be summarized by type of deviation as categorized above.   
11. 
Demographic and other Baseline Characteristics 
Demographics, including (age, gender, race, and ethnicity where applicable), and other baseline 
characteristics collected at screening, such as height, weight, body mass index, and disease 
conditions will be summarized using descriptive statistics. These data will be presented as a 
listing. Demographic data and other baseline characteristics will be presented for the safety and 
PP population. 
11.1. Derivations 
BMI (kg/ m2) = weight (kg)/ height (m)2 
Duration of epilepsy (years) = (Date of first dose - date of epilepsy onset)/365.25 
o Date of epilepsy onset: If the date of onset of epilepsy is partial, i.e. month and year 
recorded, or only year recorded, the missing component will be imputed with the last 
day of the month (where only day is missing) or 31 December (where the day and 
month are missing). If the date of onset is missing, the duration will not be calculated. 
Age (years) = (date of informed consent – date of birth)/365.25  
Baseline AEDs:   
o An AED is considered to be used at baseline if it started at any time prior to the first 
dose of study treatment and continued. Subjects may appear in multiple AED use.  


 
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12. 
Medical and Epilepsy History 
12.1. Medical History 
Medical history will be coded using (MedDRA), version 13.1, and presented for the safety 
population by SOC and PT.   
A data listing of medical history will be provided. 
12.2. Epilepsy History 
Epilepsy information will be collected and summarized descriptively for the safety population. 
Epilepsy summary will include age at onset of epilepsy in years and years since onset of epilepsy 
(refer to section 11.1 for derivation). Category of possible etiology for epilepsy will also be 
summarized.  
Listing of epilepsy history will be provided.   
13. 
Prior and Concomitant Medications 
Medications will be presented for the safety population and coded using WHO Drug version 
01MAR 2017. 
The number and percentage of subjects using each concomitant medication will be summarized 
overall according to the WHODRUG Anatomic Therapeutic Class (ATC) Level III and preferred 
term for concomitant AED and non-AED medication separately. Subjects with multiple uses of a 
concomitant medication will be counted once by the ATC level and preferred term. 
See Appendix 2 for handling of partial dates for medications, in the case where it is not possible 
to define a medication as prior, concomitant, the medication will be classified by the worst case; 
i.e. concomitant.  


 
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 Prior medications are medications which started and stopped prior to the first dose of 
study medication.  
 Concomitant medications are medications which started at the same time of or after 
the first dose of study medication and at the same time of or before the last dose of 
study medication; or started prior to and ended at the same time of or after the first 
dose of study medication; or started at the same time of or prior to the last dose of 
study medication and marked as ongoing. 
 Post-treatment medications are medications which started after the last dose of study 
medication. 
Listings of concomitant AED, non-AED medications, prior, and post-treatment medications will 
be provided. 
14. 
Study Medication Exposure 
The extent of exposure will be summarized descriptively: it will be calculated as the date of last 
dose minus the first dispensed dose date, ignoring missing days plus 1. If subject last dose is 
missing, subject last contact date will be used.  
The date of first study medication and the date of the last dose will be taken from the Study Drug 
Dispensation and Disposition source, respectively.  
Duration of exposure, the date of first dose, date of last dose, date of the change dose, amount, 
and reason for dose change will be listed.  
Frequency of duration of exposure will be summarized using the following categories: 
1 day - < 3 weeks 
=> 3 - < 7 weeks 
=> 7 - < 9 weeks 


 
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=> 9- < 11 weeks 
=> 11- < 15 weeks 
=> 15- < 17 weeks 
=> 17- < 19 weeks 
=> 19- < 23 weeks 
>= 23- <27 weeks 
> =27 – <= 31 weeks 
> 31 weeks 
14.1. Derivations 
Duration of exposure (days) = date of last study medication – date of first study medication + 1.  
15. 
Outcomes Variables 
15.1. Primary Variable 
 
Primary Variable & Derivation(s) 
The primary outcome variable is the proportion of subjects completing 24 weeks adjunctive 
therapy during Maintenance Phase (Visit 9) defined as below. 
Number of subjects who completed up to and including  the end of the 
Maintenance Phase (Visit 9/ EOS) 
 
x 100 
 
Number of subjects in the safety population  


 
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Primary Analysis of Primary Outcome Variable 
The primary analysis will be performed for the safety population. 
The number and proportion (%) of subjects completing the 24 weeks of the Maintenance Phase 
will be provided along with a 95% confidence interval using the exact method. 
It will be also summarized by age group, race group, gender, baseline AEDs and number of 
baseline AEDs. 
15.2. Efficacy Variables 
 
Efficacy Variables and Derivation 
The following periods (days) are used in the efficacy analyses: 
 Baseline:  the duration (months) recorded for the number of seizure prior to screening 
from seizure history plus the days from screening to first dose of study medication via the 
paper seizure diary.  
 Titration: date of Visit 3 (week 3) - Visit 2 (week 1) 
 Each visit intervals between Visit 3 (week 3) and Visit 9 (week 27): Visit 3 to Visit 4, 
Visit 4 to Visit 5, Visit 5 to Visit 6, Visit 6 to Visit 7, Visit 7 to Visit 8, and Visit 8 to 
Visit 9 
 First 12 weeks: date of week 15 (Visit 6)- the date of week 3 (Visit 3)  
 Last 12 weeks:  the date of week 27 (Visit 9 (EOS))- the date of week 15 
 24 weeks of the Maintenance Phase: date of week 27 (Visit 9 (EOS)) – date of week 3 
(Visit 3)  
For dropout subjects, if subject withdrew before the scheduled Visit 9(EOS), seizure data will be 
included for each interval up to the last date where the subject had data.  
Seizure related efficacy endpoints will be derived based on the paper seizure diary data. Standard 
Seizure Frequency (SSF) 


 
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Seizure frequency from the subject’s seizure diary data will be evaluated by standardizing the 
sum of seizures to a frequency per 4 weeks (28 days). 
The standardized seizure frequency (SSF) for any given period (including baseline) will be 
calculated as: 
Total number of seizures reported in the diary during the interval of 
interest 
x 28 days 
 
Number of days for the interval of interest  
 
The number of days on study for the interval of interest will be determined by: 
Visit Date of last visit during the interval of interest - Visit Date of first visit during the interval 
of interest.  Subject with missing paper seizure data in the interval of interest will not be counted 
toward the denominator.   
15.2.1.2. Relative Reduction in SSF 
Seizure frequency change from the baseline period will be evaluated by using SSF per 4 weeks 
(28 days). 
The relative (%) change from baseline in SSF is calculated as: 
SSF for the interval of interest - SSF at baseline 
x 100 
 
 
SSF at baseline  
Further the relative change from baseline will be categorized into: 
 100% Decrease 
 ≥ 75% - < 100% Decrease 


 
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 ≥ 50% - < 75% Decrease 
 0% to < 50% Decrease 
 > 0% to < 25% Increase 
 ≥ 25% to <50% increase 
 ≥ 50% to <100% increase 
 ≥ 100 % increase 
15.2.1.3. Responder Rates 
50% and 75% responder rate (≥50% and ≥75% reduction from baseline in SSF) will be calculated 
for the intervals of interest. The proportion will be calculated as the number of responders 
divided by the total number of subjects in the modified ITT population entering the period of 
interest. 
15.2.1.4. Proportion of Seizure-Free Subjects  
Subjects who did not have any seizure as per the paper seizure diary for the intervals of interest 
will be deemed seizure free, for the corresponding interval of interest.  Subjects must complete 
each interval of interest without any seizures to be considered seizure-free for each interval of 
interest. Subject with no seizure data available during interval of interest will not be considered 
seizure-free for the interval of interest. However, subjects who discontinue prior to Visit 9 will be 
considered not seizure-free for the interval when the discontinuation takes place and all 
subsequent intervals (even if the subjects are seizure-free at the time of discontinuation). Anyone 
who drops out from the study and does not complete the 24 weeks (Visit 9), is included in the 
denominator for the proportion. 
15.2.1.5. Time on ESL 
Time on ESL will be calculated from the first dose as indicated in the Study Drug Dispensation 
source to the last known dose of ESL in the Disposition source. Subjects who were still on ESL 
at the end of study will be censored at the end of study. Subjects who dropped out of the study 


 
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while receiving treatment will be an event at the time of the last dose date. Change in dosage 
levels during the treatment period will be ignored. 
 
Analysis of Efficacy Variables 
The efficacy analyses using paper seizure data will be performed for the mITT and PP 
populations, and the listings of subjects will be provided.  
Time on ESL analysis will be performed for the safety population only.  
15.2.2.2. Standard Seizure Frequency (SSF) 
The SSF will be summarized using descriptive statistics for baseline, titration, each visit intervals 
between Visit 3 and Visit 9, the first 12 weeks, the last 12 weeks, and the 24 weeks of the 
Maintenance Phase.  
Additionally, the SSF will be summarized by the subgroups presented in Section 15.3.    
15.2.2.3. Responder Rates 
The responder rates (50% and 75%) along with 95% confidence intervals (CIs) (using the exact 
method) will be presented for baseline, titration, each visit intervals between Visit 3 and Visit 9.  
Additionally, the number and percentage of subjects with the subgroups presented in Section 15.3 
will also be presented.    
15.2.2.4. Relative Reduction in SSF 
Relative (%) change in SSF from baseline will be summarized using descriptive statistics for 
baseline, titration, each visit intervals between Visit 3 and Visit 9, the first 12 weeks, the last 12 
weeks, and the 24 of the Maintenance Phase.   
The number and percentage of subjects with the subgroups presented in Section 15.3 will also be 
presented.  


 
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15.2.2.5. Proportion of Seizure-Free Subjects  
The number and proportion (%) of subject’s seizure-free along with 95% confidence intervals 
(using the exact method) will be summarized for baseline, titration, each visit intervals between 
Visit 3 and Visit 9. 
Additionally, the proportion of seizure free subjects will be summarized with the subgroups 
presented in Section 15.3.    
15.2.2.6. Time on ESL 
The median time on ESL in days and 95% CI will be estimated using Kaplan Meier time to event 
methods.  
Kaplan Meier plots for the time on ESL will be provided. 
15.3. Subgroup Analysis of Efficacy Variable(s) 
Standardized seizure frequency (SSF), and relative change (%) from baseline in SSF, will be 
summarized for mITT population, by the following subgroup variables which are defined in 
section 7.4. 
 Number of baseline AEDs 
 Baseline AEDs. 
 Seizure Type 
Responders, and proportion of seizure-free will be summarized by number of baseline AEDs and 
baseline AEDs. 
15.4. Exploratory Variables 
 
Analysis of Exploratory Variables 
The exploratory analyses will be performed for the mITT populations. 


 
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The proportions of concordance in the daily seizure frequency during the 24-weeks of the 
Maintenance Phase between the watch device and paper diary as well as between the Mate 
application and paper seizure diary for each subject will be calculated. Proportion is calculated as 
the number of days with concordance in daily seizure frequency between the two Empatica 
devices and paper seizure diary divided by the number of days with seizure frequency available 
in paper diary. The mean and 95% CI (exact method) of the proportion of the concordance will 
be provided.   
In addition, the proportion of concordance in daily seizure frequency during the 24-weeks of the 
Maintenance Phase between the Mate application and paper seizure diary will be calculated only 
with the subjects who confirmed they reported all their seizures at each day (i.e. seizure 
compliance=’Y’) in the Mate application.  
SSF will be calculated for the first 12 weeks, the last 12 weeks, and the 24 weeks of the 
Maintenance Phase using the seizure data recorded by the investigational wearable watch device, 
and MATE application from Empatica.  
The concordance correlation coefficient (CCC)1 with 95% confidence interval will be calculated 
to assess agreement in SSF during the first 12 weeks, the last 12 weeks, and the 24 weeks of the 
Maintenance Phase between the two Empatica devices and the paper seizure diary. 
The concordance correlation coefficient, rc , for measuring agreement between continuous 
variables X and Y (both approximately normally distributed), is calculated as follows: 
 
where Sxx = variance of X, Syy = variance of Y, Sxy=covariance of X and Y. 
This is a measure of how well a set of data (Y) compares to a “gold standard” measurement or 
test (X).   It measures both the precision (similar to Pearson’s correlation coefficient), and 
accuracy (i.e. how far away results are from a 45-degree line through the origin, or from perfect 
concordance) of the association. 


 
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. Similar to the other correlation coefficient, the concordance correlation satisfies -1 ≤ rc ≤ +1. A 
value of rc = +1 corresponds to perfect agreement. A value of rc = - 1 corresponds to perfect 
negative agreement, and a value of rc = 0 corresponds to no agreement.  
Scatter plots of the above SSFs using the seizure data recorded by the watch device as well as 
Mate application and by those from the paper seizure diary will be presented to evaluate 
agreement graphically. 
15.5. Quality of Life Analysis  
Quality of Life (QoL) analyses will be performed for the safety population. 
 
Variables & Derivations 
15.5.1.1. EuroQol Five Dimensions Questionnaire (EQ-5D) scores 
The EQ-5D is made up of two components, health state description and overall health evaluation. 
In the description part, health status is measured in terms of five dimensions (5D):  
1. Mobility dimension asks about the person’s walking ability 
1. I have no problems walking 
2. I have slight problems walking 
3. I have moderate problems walking 
4. I have severe problems walking 
5. I am unable to walk 
2. Self-care dimension asks about the ability to wash or dress by oneself 
1. I have no problems washing or dressing myself 
2. I have slight problems washing or dressing myself 
3. I have moderate problems washing or dressing myself 
4. I have severe problems washing or dressing myself 
5. I am unable to wash or dress 


 
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3. Usual activities dimension measures performance in “work, study, housework, family or 
leisure activities” 
1. I have no problems doing my usual activities 
2. I have slight problems doing my usual activities 
3. I have moderate problems doing my usual activities 
4. I have severe problems doing my usual activities 
5. I am unable to do my usual activities 
4. Pain/discomfort dimension, it asks how much pain or discomfort they have 
1. I have no pain or discomfort 
2. I have slight pain or discomfort 
3. I have moderate pain or discomfort 
4. I have severe pain or discomfort 
5. I have extreme pain or discomfort 
5. Anxiety/depression dimension, it asks how anxious or depressed they are 
1. I am not anxious or depressed 
2. I am slightly anxious or depressed 
3. I am moderately anxious or depressed 
4. I am severely anxious or depressed 
5. I am extremely anxious or depressed 
The respondents self-rate their level of severity for each dimension using a 5-level scale: no 
problems, slight problems, moderate problems, severe problems and extreme problems.  
In addition, the respondents evaluate their overall health status using the visual analogue scale. 
This scale is numbered from 0 to 100. 0 means the worst health you can imagine and 100 means 
the best health you can imagine. 


 
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15.5.1.2. Clinical Global Impression (CGI) – Improvement 
The CGI-I scale is a 7-point scale that requires an approved rater to assess how much the 
patient’s illness has improved or worsened relative to a baseline state at the beginning of the 
intervention and rated as:  
1. Very Much Improved 
2. Much Improved 
3. Minimally Improved 
4. No Change 
5. Minimally Worse 
6. Much Worse 
7. Very Much Worse 
15.5.1.3. Patient Global Impression of Change (PGIC) 
The PGI-C is a 7-point scale that requires the subject to assess the change (if any) in activity 
limitations, symptoms, emotions and overall quality of life.  
The subject responses include:   
1. No change (or condition has gotten worse) 
2. Almost the same, hardly any change at all  
3. A little better, but no noticeable change  
4. Somewhat better, but the change has not made any real difference 
5. Moderately better, and a slight but noticeable change  
6. Better, and a definite improvement that has made a real and worthwhile difference  
7. A great deal better, and a considerable improvement that has made all the difference 
15.5.1.4. Quality of Life in Epilepsy-Patient-Weighted (QOLIE-31-P) 
The QOLIE-31-P contains seven multi-item scales that investigate the following health concepts:  
1. Emotional Well-Being 


 
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2. Social Functioning 
3. Energy/Fatigue 
4. Cognitive Functioning 
5. Seizure Worry 
6. Medication Effects  
7. Overall Quality of Life (QOL) 
The QOLIE-31-P overall score is obtained by using a weighted average of the multi-item scale 
scores.  The QOLIE-31-P also includes a single item that assesses overall health on a visual 
analogue scale.  The recorded responses will be converted to 0 -100-point scales as described in 
Table 3. The mean of the individual item scores in each subgroup are then calculated, with higher 
converted scores reflecting better quality of life. If one item within a scale score is missing, it will 
be replaced by the mean value of the other items.  If more than one item is missing, the scale 
score will not be calculated.   
The QOLIE-31-P overall score is obtained by using a weighted average of the 7 scale scores 
according to the following formula: 
 
Overall score = Seizure worry * 0.08 
 
 
 
+ Overall quality of life * 0.14 
 
 
 
+ Emotional well-being * 0.15 
 
 
 
+ Energy/fatigue * 0.12 
 
 
 
+ Cognitive functioning * 0.27 
 
 
 
+ Medication effects * 0.03 
 
 
 
+ Social functioning * 0.21 
Table 3:  QOLIE-31 Response Conversions 
Scale 
Response 
Formula 


 
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    Item Numbers 
1 
2 
3 
4 
5 
6 
Seizure Worry 
 
 
 
 
 
 
 
    11. 
0 
20 
40 
60 
80 
100 
((Resp-1)/(Max-1)*100 
    21. 
0 
33.3 
66.7 
100 
- 
- 
((Resp-1)/(Max-1)*100 
    22. 
0 
50 
100 
- 
- 
- 
((Resp-1)/(Max-1)*100 
    23. 
0 
33.3 
66.7 
100 
- 
- 
((Resp-1)/(Max-1)*100 
    25. 
100 
75 
50 
25 
0 
- 
100-((Resp-1)/(Max-
1))*100 
Overall Quality of 
Life 
 
 
 
 
 
 
 
    1. 
Multiply response by 10 
 
    14. 
100 
75 
50 
25 
0 
- 
100-((Resp-1)/(Max-
1))*100 
Emotional Well-
being 
 
 
 
 
 
 
 
    3. 
0 
20 
40 
60 
80 
100 
((Resp-1)/(Max-1)*100 
    4. 
0 
20 
40 
60 
80 
100 
((Resp-1)/(Max-1)*100 
    5. 
100 
80 
60 
40 
20 
0 
100-((Resp-1)/(Max-
1))*100 
    7. 
0 
20 
40 
60 
80 
100 
((Resp-1)/(Max-1)*100 


 
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    9. 
100 
80 
60 
40 
20 
0 
100-((Resp-1)/(Max-
1))*100 
Energy/Fatigue 
 
 
 
 
 
 
 
    2. 
100 
80 
60 
40 
20 
0 
100-((Resp-1)/(Max-
1))*100 
    6. 
100 
80 
60 
40 
20 
0 
100-((Resp-1)/(Max-
1))*100 
    8. 
0 
20 
40 
60 
80 
100 
((Resp-1)/(Max-1)*100 
    10.   
0 
20 
40 
60 
80 
100 
((Resp-1)/(Max-1)*100 
Cognitive 
Functioning 
 
 
 
 
 
 
 
    12. 
0 
20 
40 
60 
80 
100 
((Resp-1)/(Max-1)*100 
    15. 
0 
33.3 
66.7 
100 
- 
- 
((Resp-1)/(Max-1)*100 
    16. 
0 
20 
40 
60 
80 
100 
((Resp-1)/(Max-1)*100 
    17. 
0 
20 
40 
60 
80 
100 
((Resp-1)/(Max-1)*100 
    18. 
0 
20 
40 
60 
80 
100 
((Resp-1)/(Max-1)*100 
    26. 
100 
75 
50 
25 
0 
- 
100-((Resp-1)/(Max-
1))*100 
Medication Effects 
 
 
 
 
 
 
 
    24. 
0 
33.3 
66.7 
100 
- 
- 
((Resp-1)/(Max-1)*100 
    29. 
100 
75 
50 
25 
0 
- 
100-((Resp-1)/(Max-
1))*100 


 
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    30. 
100 
75 
50 
25 
0 
- 
100-((Resp-1)/(Max-
1))*100 
Social Functioning 
 
 
 
 
 
 
 
    13. 
0 
20 
40 
60 
80 
100 
((Resp-1)/(Max-1)*100 
    19. 
0 
25 
50 
75 
100 
- 
((Resp-1)/(Max-1)*100 
    20. 
0 
25 
50 
75 
100 
- 
((Resp-1)/(Max-1)*100 
    27. 
100 
75 
50 
25 
0 
- 
100-((Resp-1)/(Max-
1))*100 
    28. 
100 
75 
50 
25 
0 
- 
100-((Resp-1)/(Max-
1))*100 
Resp=Response, Max=Maximum possible response for the respective item. 
15.5.1.5. Profile of Mood States Short-form (POMS-SF) 
The POMS-SF is an instrument designed to assess transient, distinct mood states and consists of a 
list of 37 adjectives. Respondents indicate the degree to which each adjective describes 
themselves during the last week using a 5-point Likert scale:0= not at all, 1=a little, 
2=moderately, 3=quite a bit, and 4=extremely. This format yields both an overall Total Mood 
Disturbance score as well as scores for each of the six subscales contained in the original POMS:  
The items included in 6 subscales are 
1. Fatigue-Inertia: worn-out, fatigued, exhausted, weary, bushed 
2. Vigor-Activity:  lively, active, energetic, cheerful, full of pep, vigorous 
3. Tension-Anxiety: Tense, on edge, uneasy, restless, nervous, anxious 
4. Depression-Dejection: unhappy, sad, blue, hopeless, discouraged, miserable, helpless, 
worthless 


 
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5. Anger-Hostility: angry, peeved, grouchy (written as grovely in some versions), annoyed, 
resentful, bitter, furious 
6. Confusion-Bewilderment: confused, unable to concentrate, bewildered, forgetful, 
uncertain about things 
Each subscale will be calculated by summing the point for items.  The total mood disturbance 
score will be calculated by summing the total for the negative subscales and then subtracting the 
total for the positive subscale: Depression-Dejection + Tension-Anxiety + Anger-Hostility + 
Fatigue-Inertia + Confusion-Bewilderment -Vigor-Activity + 100. A constant (e.g. 100) will be 
added to total mood score in order to eliminate negative scores. 
15.5.1.6. Neurological Disorders Depression Inventory for Epilepsy (NDDI-E) 
The NDDI-E is a 6-item questionnaire validated to screen for depression in people with epilepsy. 
The NDDI-E consists of the following items: 
1. Everything is a struggle 
2. Nothing I do is right 
3. Feel guilty 
4. I’d be better off dead 
5. Frustrated 
6. Difficulty finding pleasure 
Each item is rated on a 4-point Likert scale (1=never, 2=rarely, 3=sometimes, 4=always or often) 
with higher scores indicating a more severe response. Total Score is defined as the summation of 
all individual item scores. NIDDI-E scores ≥16 are considered positive for depression2. 
15.5.1.7. Modified Overt Aggression Scale (MOAS) 
The MOAS is divided in four domains: 1. verbal aggression, 2. aggression against objects, 3 
aggression against self, and 4 aggression against other people. A score from 0 to 4 is assigned to 
each act: 0 indicates no aggressive behavior and higher scores indicate increasing severity.  


 
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Section scores are weighted as follows: Scores from the “Verbal Aggression” section multiplied 
by 1; Scores from the “Aggression Against Property” section multiplied by 2; Scores from the 
“autoaggression” section multiplied by 3; Scores from the “physical aggression” section 
multiplied by 4. Weighted scores are then added together to get the total score. Total scores on 
the MOAS range from 0 to 40, with a higher score indicating more aggressive behavior. 
Verbal Aggression: 
0. No verbal aggression  
1. Shouts angrily, curses mildly, or makes personal insults  
2. Curses viciously, is severely insulting, has temper outbursts  
3. Impulsively threatens violence toward others or self  
4. Threatens violence toward others or self repeatedly or deliberately (e.g., to gain money or 
sex) 
Aggression Against Property: 
0. No aggression against property  
1. Slams door angrily, rips clothing, urinates on floor  
2. Throws objects down, kicks furniture, defaces walls  
3. Breaks objects, smashes windows  
4. Sets fires, throws objects dangerously 
Autoaggression:  
0. No autoaggression  
1. Picks or scratches skin, pulls hair out, hits self (without injury)  
2. Bangs head, hits fists into walls, throws self on floor  


 
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3. Inflicts minor cuts, bruises, burns or welts on self  
4. Inflicts major injury on self or makes a suicide attempt 
Physical Aggression:  
0. No physical aggression  
1. Makes menacing gestures, swings at people, grabs at clothing  
2. Strikes, pushes, scratches, pulls hair of others (without injury)  
3. Attacks others, causing mild injury (bruises, sprains, welts, etc.)  
4. Attacks others, causing serious injury (fracture, loss of teeth, deep cuts, loss of 
consciousness, etc.) 
 
Analysis of QOL Variables 
15.5.2.2. Analysis of EuroQol Five Dimensions Questionnaire (EQ-5D)  
The EQ-5D overall health status, visual analogue scale (VAS) scores, observed and changes from 
baseline for each evaluation time point will be summarized descriptively by arm.  
The number and percentage of subjects for each health state description will be summarized by 
each evaluation timepoint and Arm. In addition shift table for each evaluation time point will be 
summarized by arm.  
Figure of the mean (+/-SD) change from baseline for overall health (VAS) scores will be 
provided.  
Listing of EQ-5D scores including score of each individual item will be provided. 


 
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15.5.2.2. Analysis of Clinical Global Impression of Improvement (CGI-I)   
Frequency and percentage of Clinical Global Impression of Improvement (CGI-I) scores at each 
evaluation time point will be summarized by arm.  
Listing of CGI-I scores will also be provided. 
15.5.2.3. 
Analysis of Patient's Global Impression of Change (PGI-C)  
Frequency and percentage of Patient’s Global Impression of Change (PGI-C) scores for each 
evaluation time point will be summarized by arm. 
Listing of PGI-C scores will also be provided. 
15.5.2.4. 
Analysis of Quality of Life in Epilepsy-Patient-Weighted (QOLIE-31-P) 
The QOLIE-31-P overall scores, global assessment and subscale scores, observed and changes 
from baseline in the score for each evaluation time point will be summarized descriptively by 
arm.  
Figure of the mean (+/-SD) change from baseline for the total score by time point and arm will be 
provided. 
Listing of QOLIE-31-P scores including each individual scoring item will be provided. 
15.5.2.5. Analysis of Profile of Mood States Short-form (POMS-SF) 
The POMS-SF total mood disturbance scores and subscale scores, observed and changes from 
baseline in the score of each evaluation time point will be summarized descriptively.  
Figure of the mean (+/-SD) change from baseline for the total mood disturbance score by time 
point and arm will be provided. 
Listing of POMS-SF scores including score of each individual item will be provided. 


 
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15.5.2.6. Analysis of Neurological Disorders Depression Inventory (NDDI-E) 
The NDDI-E total scores and individual item scores, observed and changes from baseline in the 
score of each evaluation time point will be summarized descriptively.  
The number of subjects with total score<16 and ≥16 will be presented by time point and arm. 
Figure of the mean(+/-SD) change from baseline for the total score by time point and arm will be 
provided. 
Listing of NDDI-E scores will also be provided. 
15.5.2.7. Analysis of Modified Overt Aggression Scale (MOAS) 
The MOAS total scores and domain scores, observed and changes from baseline for each 
evaluation time point will be summarized descriptively by arm.  
Figure of the mean (+/-SD) change from baseline for the total score by time point and arm will be 
provided. 
Listing of MOAS scores including score of each individual item will be provided. 
16. 
Safety Outcomes 
All outputs for safety outcomes will be based on the safety population.  
16.1. 
Pre-treatment and Adverse Events 
Pre-treatment events will be monitored from the time informed consent form (ICF) is provided up 
until the date of first ESL dose. 
AEs will be monitored from the date of first ESL dose. 
Serious adverse events will be monitored from the time informed consent/assent is obtained. 


 
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All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) version 
13.1.  
AEs are untoward medical occurrences: 
 that occurred on or after the first dose of study medication. 
 with a missing start date and a stop date on or after the first dose of study medication, OR 
 with both a missing start and stop date. 
See Appendix 2 for handling of partial dates for AEs. 
 
All AEs  
Incidence of AEs and number of events will be presented by arm, System Organ Class (SOC) and 
Preferred Term (PT). AEs will be presented by maximum severity and relationship to study 
medication as specified in the sections below.  
For subject incidence summaries, each subject will be counted only once within each SOC and 
within each PT. All AEs will be summarized overall and by age group, race group, gender, 
baseline AEDs and number of baseline AEDs. 
Listing of all AEs and pre-treatment AEs will be provided. 
 
 
Severity 
Severity is classed as mild/ moderate/ severe (increasing severity). AEs starting after the first 
dose of study medication with a missing severity will be classified as severe. If a subject reports 
an AE more than once within that SOC/ PT, the AE with the highest known severity will be used 
in the corresponding severity summaries. 


 
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Relationship to Study Medication 
Relationship, as indicated by the Investigator, is classed as “not related”, “possible”, “probable” 
(increasing severity of relationship) or “definite”. 
For summaries by relationship to the study medication, AEs will be grouped as “related” or “not 
related.” 
 AE Related:  AEs with relationship to study medication assessed as “possible,” 
“probable,” or “definite”  
 AE not Related:  AEs with relationship to study medication assessed as “not related”  
 AEs with a missing relationship to study medication will be regarded as related 
 If a subject report the same AE more than once within that SOC/ PT, the AE with the worst-case 
relationship to study medication will be used in the corresponding relationship summaries.  
 
AEs Leading to Discontinuation of Study Medication 
For AEs leading to discontinuation of study medication, summaries of incidence (numbers and 
percentages) by SOC and PT will be provided. 
Listing of AEs leading to discontinuation will be provided. 
 
Serious Adverse Events 
Serious adverse events (SAEs) are those events recorded as” Serious” on the Adverse Events 
source.  
Incidence of SAEs and number of events will be presented by arm, SOC and PT.  
All SAEs will be summarized overall and by age group, race group, gender, baseline AEDs and 
number of baseline AEDs. 
Additionally, listing of SAEs will be provided. 


 
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Non-Serious Adverse Events  
Incidence of non-SAEs and number of events will be presented by arm, System Organ Class 
(SOC) and Preferred Term (PT).  
 
Adverse Events Leading to Death 
AEs leading to Death are those events which are recorded with outcome of” Fatal” on the 
Adverse Events source. A summary of AEs leading to death by SOC and PT will be prepared.  
Listing of deaths will be provided. 
16.2. Laboratory Evaluations 
Results from the central laboratory will be included in the reporting of this study for Hematology, 
Blood Chemistry, Urinalysis, Thyroid Panel, Renal Functioning, Urine Drug Screening, Serum 
Pregnancy and Urine Pregnancy Test.  A list of laboratory assessments to be included in the 
outputs is included in Appendix 1 of the protocol, Section 20.  
All laboratory summaries will be used on the safety population and presentations will use SI 
Units.  
Quantitative laboratory measurements reported as “< X”, will be converted to X for the purpose 
of quantitative summaries, but will be presented as recorded, i.e. as “< X” or “> X” in the 
listings. The following summaries and listings will be provided for laboratory data: 
 For laboratory parameters with continuous outcomes (e.g. blood chemistry, hematology, 
urinalysis data, thyroid panel), descriptive statistics for the actual values and for changes 
from baseline will be presented by arm for each evaluation time point. 
 For laboratory parameters with categorical outcomes (e.g. urinalysis data), the number 
and percentage of subjects with each outcome will be presented by arm at each evaluation 
time point. 
 Overall summary of the post-bassline PCS will be presented.  The number and percentage 
of subjects with PCS criteria will be summarized by arm  . This summary will be also 


 
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presented by age group, race group, gender, baseline AEDs and number of baseline 
AEDs. 
 Shifts from baseline by arm for each evaluation time point will be produced to show the 
percentage of subjects with laboratory test values below, within, and above the normal 
range. 
 Data listing of all clinical laboratory measurements (hematology, blood chemistry, 
urinalysis, thyroid, and renal function) will be provided.  Results outside of the reference 
range will be flagged.  
 Listing of clinically significant out of range laboratory measurements, urine drug screen 
and serum pregnancy test results will be provided. 
 A listing of PCS laboratory findings (e.g. blood chemistry, hematology, urinalysis data, 
and thyroid function) will be presented for all laboratory parameters with PCS criteria 
defined in Appendix 3. 
 
Blood Sodium Levels   
In addition to descriptive summaries of blood sodium levels and changes from baseline for each 
assessment time point, the number and percentage of subjects with normal baseline sodium level 
(i.e. >135 mEq/L) reaching ≤ 135 mEq/L but > 130 mEq/L, ≤ 130 mEq/L but > 125 mEq/L, ≤ 
125 mEq/L, and > 10 mEq/L reduction (ie, < -10 mEq/L) from baseline will be summarized by 
arm for each evaluation time point and overall post-baseline. 
 
Laboratory Reference Ranges and Potentially Clinically Significant (PCS) 
Quantitative laboratory measurements will be compared with the relevant laboratory reference 
ranges in SI units and categorized as: 
Low: Below the lower limit of the laboratory reference range.  
Normal: Within the laboratory reference range (upper and lower limit included). 
High: Above the upper limit of the laboratory reference range. 


 
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Similarly, sponsor defined- PCS laboratory results will be identified using the criteria in 
Appendix 3. 
16.3. ECG Evaluations 
The number and percentage of subjects with ECG results  will be presented as Normal, Abnormal 
and Not Evaluable. A subject will be counted in the worst result for the post-baseline value. 
ECG results  will be presented in a data listing. 
16.4. Vital Signs 
Vital signs (supine systolic and diastolic blood pressures, respiratory rate, pulse rate, and oral 
temperature) and weight will be summarized using descriptive statistics at baseline and each 
evaluation visit. Change from baseline will be included in this presentation as well. In addition, 
the number and percentage of subjects with vital sign PCS criteria in Table 4 will be presented. 
Data listings of vital signs and PCS criteria will be provided.  
Table 4. Vital Signs Potentially Clinically Significant (PCS) Criteria 
Variable 
Unit 
Low 
High 
Supine SBP 
mmHg 
< 90 mmHg AND  
change from baseline 
≤ -20 mmHg 
> 180 mmHg AND 
change from baseline ≥ 20 mmHg 
Supine DBP 
mmHg 
< 50 mmHg AND 
change from ≤ -15 mmHg 
> 105 mmHg AND 
change from baseline ≥ -15 mmHg 
Supine Pulse 
rate 
beats/min 
< 50 bpm AND 
change from baseline ≤ -15 
bpm 
> 120 bpm AND 
change from baseline ≥ 25 bpm 


 
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Variable 
Unit 
Low 
High 
Weight 
Kg 
percentage change from 
baseline ≤ -7.0 % 
percentage change from baseline ≥ 7.0 % 
16.5. Physical/Neurological Examination  
All physical and neurological exam findings at screening will be captured in the medical history 
and summarized together with the other medical history events. Clinically significant changes 
from the screening visit will be captured as AEs as appropriate and summarized together with the 
other AEs. A listing displaying whether a physical examination was performed for each subject 
and the date of the physical examination will be provided.   
16.6. Other Safety Assessments 
 
Electronic Columbia Suicide Severity Rating Scale (eC-SSRS) 
The eC-SSRS is a tool designed to systematically assess and track suicidal behavior and suicidal 
ideation for life time prior to the screening visit, and throughout the study. The strength of this 
suicide classification system is in its ability to comprehensively identify suicidal events while 
limiting the over-identification of suicidal behavior. The eC-SSRS Baseline/Screening Version is 
used at the screening visit and the eC-SSRS Since Last Visit Version is used from Visit 2 
onward.  
Subjects with complete and incomplete eC-SSRS records in the same visit, both records will be 
included in the listing.  
Subjects who have complete and incomplete eC-SSRS records in the same visit, only complete 
records will be included in the summary tables. otherwise the incomplete record will be included 
in the tables.  
eC-SSRS includes four sections: Suicidal Ideation, Intensity of Ideation, Suicidal Behavior, and 
Answer for Actual Suicide Attempts.  


 
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The following outcomes are eC-SSRS categories and have binary responses (yes/no). The 
categories are re-ordered from the scale to facilitate the definitions of the eC-SSRS endpoints, 
and to provide clarity in the presentation of the results. 
Suicidal ideation is measured by 5 categories, representing 5 subtypes of suicidal ideation with 
increasing severity: 
1. Category 1: Wish to be Dead 
2. Category 2: Non-specific Active Suicidal Thoughts 
3. Category 3: Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
4. Category 4: Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
5. Category 5: Active Suicidal Ideation with Specific Plan and Intent 
Suicidal behavior is measured by 5 categories, representing 5 subtypes of suicidal behavior: 
1. Category 6: Preparatory Acts or Behavior 
2. Category 7: Aborted Attempt 
3. Category 8: Interrupted Attempt 
4. Category 9: Actual Attempt (non-fatal) 
5. Category 10: Completed Suicide 
The 10 categories above are not mutually exclusive. Subjects will be counted in each category for 
which they have an event. 
Self-injurious behavior without suicidal intent is a non-suicide-related eC-SSRS outcome, and 
has a binary response (yes/no). 
For eC-SSRS analysis, “baseline” and “post-baseline” are defined as follows. 
Time point 
Study Visit 
eC-SSRS Version 
Derivation Rule 
Baseline 
Screening/Visit 1 
Baseline/Screening – life time, past one 
months and past two years 
Most severe 
outcome 
Titration/Visit 2 
Since Last Visit 


 
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Post-
baseline 
All post-baseline visits up 
to and including Week 
27/Visit 9, including 
unscheduled visits 
Since Last Visit 
Most severe 
outcome 
eC-SSRS composite endpoints will be derived for each time point of interest (i.e. baseline, post 
baseline, and each study visit) as follows: 
Any suicidal ideation: A “yes” answer to any one of the 5 suicidal ideation questions on eC-
SSRS (Categories 1-5). 
Any suicidal behavior: A “yes” answer to any one of the 5 suicidal behavior questions on the eC-
SSRS (Categories 6-10). 
Any suicidality: A “yes” answer to any one of the 10-suicidal ideation and behavior questions on 
the eC-SSRS (Categories 1-10). 
For each subject, the suicidal ideation score at each time point of interest (i.e. baseline, post 
baseline, and each study visit) is defined as the maximum suicidal ideation category (1-5) present 
for the time of interest. If no ideation is present a score of 0 is assigned. A suicidal ideation score 
of 4 or 5 is considered serious. 
The number and percentage of subjects with any suicidality, any suicidal ideation and subtypes of 
ideation, any suicidal behavior and subtypes of behavior, and any non-suicidal self-injurious 
behavior will be presented for: 
 Baseline (as defined above) 
 Post-baseline (as defined above) 
 Each scheduled study visit: Screening (lifetime), Titration/Visit 2, Week 3/Visit 3, Week 
7/Visit 4, Week 11/Visit 5, Week 15/Visit 6, Week 19/Visit 7, Week 23/Visit 8, Week 
27/Visit 9, EDV. 


 
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Shift in suicidal ideation score from baseline to the post-baseline time point and to each the 
following study visit will be presented: Week 3/Visit 3, Week 7/Visit 4, Week 11/Visit 5, Week 
15/Visit 6, Week 19/Visit 7, Week 23/Visit 8, Week 27/Visit 9, EDV.  
Intensity of ideation for the most severe ideation subtype is measured in terms of frequency, 
duration, controllability, deterrents, and reasons for ideation. Each is measured with responses 
ranging from 0 to 5 for frequency and duration, and from 1 to 5 for controllability, deterrents, and 
reasons for ideation. The ideation intensity total score is the sum of responses to the five items 
and can range from 2 to 25 for subjects with endorsed suicidal ideation. If one or more of these 
five items are missing at an assessment, the total score will be set to missing. If a subject did not 
endorse any suicidal ideation, a score of 0 for the ideation intensity total score will be given. 
Actual lethality associated with actual attempts is rated on a 6-point scale from 0 = ‘No physical 
damage or very minor physical damage’ to 5 = ‘Death’. Potential lethality of actual attempts (if 
actual lethality = 0) is rated on a 3-point scale from 0 = ‘Behavior not likely to result in injury’ to 
2 = ‘Behavior likely to result in death despite available medical care. 
The ideation intensity total score and the actual lethality and potential lethality of actual attempts 
will be presented in data listings. 
 
Score of AED-specific AEs (by the Liverpool Adverse Event Profile [LAEP]). 
The LAEP is designed as a patient self-report scale to assess the frequency of AED side effects. It 
includes 19 items rated on a 4-point Likert scale with 1, never a problem; 2, rarely a problem; 3, 
sometimes a problem; and 4, always or often a problem. Total scores range from 19 to 76, with 
high scores indicating more-frequent symptom reporting. 
The LAEP is introduced to the participants in the questionnaire with the heading “Here are a few 
questions about your health generally.” The recommended preamble to the scale followed with 
the words, “During the last 4 weeks, have you had any of the problems listed.” The problems 
include unsteadiness, tiredness, restlessness, feelings of anger or aggression to others, 
nervousness and/or agitation, headache, hair loss, problems with skin (eg, acne, rash), double or 


 
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blurred vision, upset stomach, difficulty in concentrating, trouble with mouth or gums, shaky 
hands, weight gain, dizziness, sleepiness, depression, memory problems, and disturbed sleep. 
The following summaries and listings will be provided for LAEP data: 
 The individual LAEP scores and changes from baseline for each evaluation time point 
will be summarized for each symptom descriptively.  
 The total score and change from baseline will be also summarized.  
 A listing of LAEP will be provided. 
Figure of the mean (+/-SD) change from baseline for the total score by time point and arm will be 
provided. 


 
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17. 
References  
1. A Concordance Correlation Coefficient to Evaluate Reproducibility, L. Lin, Biometrics, 
Vol. 45, No. 1 (Mar., 1989), 255-268  
2.  Identifying depression in epilepsy in a busy clinical setting is enhanced with systematic 
screening, D. Friedman et al, Seizure, 18, 2009, 429-433. 
3. SAS Institute Inc. 2009. Base SAS® 9.2 Procedures Guide. Cary, NC: SAS Institute Inc.  
4. Base SAS® 9.2 Procedures Guide. Copyright © 2009 by SAS Institute Inc., Cary, NC, 
USA. 
 
 
 
 


 
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Appendix 1. Programming Conventions for Outputs 
Dates & Times 
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
Presentation of Arm 
For outputs, group will be represented as follows and in that order: 
Group 
For Tables, Listings and Graphs 
Arm 1 
Arm 1 
Arm 2 
Arm 2 
Presentation of Visits 
For outputs, visits will be represented as follows and in that order: 
Long Name (default) 
Short Name  
Screening (Visit 1) 
Scr (V1) 
Baseline (Visit 2) 
BL (V2) 
Week 3 (Visit 3) 
W3 (V3) 
Week 7 (Visit 4) 
W7(V4) 
--- 
--- 
Week 23 (Visit 8) 
W23 (V8) 
Week 27 (Visit 9)  
W27 (V9/EOS) 
Early Discontinuation Visit 
EDV 
Week 31 (Visit 10) 
W31 (V10) 
 


 
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Listing Order 
All listings will be ordered by the following (unless otherwise indicated in the template): 
 Center-subject ID,  
 Date (where applicable) 


 
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Appendix 2. Partial Date Conventions 
Imputed dates will NOT be presented in the listings. 
Algorithm for Adverse Events: 
START DATE 
STOP 
DATE 
ACTION 
Known 
Known 
If start date < study med start date, then not AE 
If start date >= study med start date, then AE 
Partial 
If start date < study med start date, then not AE 
If start date >= study med start date, then AE 
Missing 
If start date < study med start date, then not AE 
If start date >= study med start date, then AE 
 
 
 
Partial, but known 
components show that it 
cannot be on or after 
study med start date 
Known 
Pre-treatment events 
Partial 
Pre-treatment events 
Missing 
Pre-treatment events 
 
 
 
Partial, could be on or 
after study med start date 
Known 
If stop date < study med start date, then Pre-treatment events 
If stop date >= study med start date, then AE 
Partial 
Impute stop date as latest possible date (i.e. last day of month if 
day unknown or 31st December if day and month are 
unknown), then: 
If stop date < study med start date, then Pre-treatment events 
If stop date >= study med start date, then AE 
Missing 
Assumed AE 
 
 
 
Partial, and known 
components show that it 
Known 
AE 
Partial 
AE 
Missing 
AE 


 
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START DATE 
STOP 
DATE 
ACTION 
is on or after 361-201 
study med start date 
 
 
 
Missing 
Known 
If stop date < study med start date, then Pre-treatment events 
If stop date >= study med start date, then AE 
Partial 
Impute stop date as latest possible date (i.e. last day of month if 
day unknown or 31st December if day and month are 
unknown), then: 
If stop date < study med start date, then not AE 
If stop date >= study med start date, then AE 
Missing 
Assumed AE 
 
 
 


 
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Algorithm for Prior / Concomitant Medications:  
START 
DATE 
STOP 
DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior  
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant  
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
Partial 
Impute stop date as latest possible date: 
 If only day unknown, impute as the earlier of (last day of month, 
end date of the last study visit) 
 If month and day unknown, impute as the earlier of (31st 
December, end date of the last study visit). 
Then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant 
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 


 
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START 
DATE 
STOP 
DATE 
ACTION 
Partial 
Known 
Impute start date as earliest possible date: Source questions: ‘started prior 
to start of study?’ = Yes; ‘Started after last dose of study medication?’ = 
No.  
 If only day unknown, impute as the later of (first day of the month). 
 If month and day unknown, impute as the later of (1st January).  
Source questions: ‘Started prior to study?’ = No; ‘Started after last dose of 
study medication?’ = Yes.  
 If only day unknown, impute as the later of (first day of the month; 
end of treatment + 1).  
 If month and day unknown, impute as the later of (1st January; end 
of treatment + 1).  
Source questions: ‘Started prior to study?’ = No; ‘Started after last dose of 
study medication?’ = No.  
 If only day unknown, impute as the later of (first day of the month; 
date of ICF).  
 If month and day unknown, impute as the later of (1st January; date 
of ICF).  
Then:  
If stop date < study med start date, assign as prior.  
If stop date >= study med start date and start date <= end of treatment, 
assign as concomitant.  
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment. 
 
treatment, assign as concomitant.  
If stop date >= study med start date and start date > end of treatment, 
assign as post treatment. 
Partial 
 


 
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START 
DATE 
STOP 
DATE 
ACTION 
 
Impute start date as earliest possible date: Source questions: ‘Started prior 
to study?’ = Yes; ‘Started after last dose of study medication?’ = No.  
• If only day unknown, impute as the later of (first day of the month; date 
of birth).  
• If month and day unknown, impute as the later of (1st January).  
Source questions: ‘Started prior to study?’ = No; ‘Started after last dose of 
study medication?’ = Yes.  
• If only day unknown, impute as the later of (first day of the month; end of 
treatment + 1).  
• If month and day unknown, impute as the later of (1st January; end of 
treatment + 1).  
Source questions: ‘Started prior to study?’ = No; ‘Started after last dose of 
study medication?’ = No.  
• If only day unknown, impute as the later of (first day of the month; date 
of ICF).  
• If month and day unknown, impute as the later of (1st January; date of 
ICF).  
Impute stop date as latest possible date:  
• If only day unknown, impute as the earlier of (last day of the month; end 
date of the last study visit).  
assign as prior. If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant. If stop date >= study med start date and 
start date > end of treatment, assign as post treatment. 


 
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START 
DATE 
STOP 
DATE 
ACTION 
 
• If month and day unknown, impute as the earlier of (31st December; end 
date of the last study visit).  
Then:  
If stop date < study med start date, assign as prior. If stop date >= study 
med start date and start date <= end of treatment, assign as concomitant. If 
stop date >= study med start date and start date > end of treatment, assign 
as post treatment. 
Missing 
Impute start date as earliest possible date:  
Source questions: ‘Started prior to study?’ = Yes; ‘Started after last dose of 
study medication?’ = No.  
• If only day unknown, impute as the later of (first day of the month; date 
of birth).  
• If month and day unknown, impute as the later of (1st January).  
Source questions: ‘Started prior to study?’ = No; ‘Started after last dose of 
study medication?’ = Yes.  
• If only day unknown, impute as the later of (first day of the month; end of 
treatment + 1).  
• If month and day unknown, impute as the later of (1st January; end of 
treatment + 1).  
Source questions: ‘Started prior to study?’ = No; ‘Started after last dose of 
study medication?’ = No.  
• If only day unknown, impute as the later of (first day of the month; date 
of ICF). 
• If month and day unknown, impute as the later of (1st January; date of 
ICF).  
Then: If stop date is missing could never be assumed a prior medication.  
If start date <= end of treatment, assign as concomitant.  
If start date > end of treatment, assign as post treatment.  
 
 
 


 
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START 
DATE 
STOP 
DATE 
ACTION 
Missing 
Known 
If stop date < study med start date, assign as prior.  
If stop date >= study med start date and Source question ‘Started after last 
dose of study medication?’ = No, assign as concomitant.  
If Source question ‘Started after last dose of study medication?’ = Yes, 
assign as post treatment. 
 
Partial 
Impute stop date as latest possible date:  
• If only day unknown, impute as the earlier of (last day of the month; end 
date of the last study visit). 
 • If month and day unknown, impute as the earlier of (31st December; end 
date of the last study visit).  
Then: If stop date < study med start date, assign as prior. 
 If stop date >= study med start date and CRF question ‘Started after last 
dose of study medication?’ = No, assign as concomitant.  
If Source question ‘Started after last dose of study medication?’ = Yes, 
assign as post treatment. 
 
Missing 
If Source question ‘Started after last dose of study medication?’ = No, 
assign as concomitant.  
If Source question ‘Started after last dose of study medication?’ = Yes, 
assign as post treatment. 
 
 
 


 
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Appendix 3.  PCS Criteria for Laboratory Parameters 
Category 
 Parameter Name  
  Gender Restriction, if any 
 
 
PCS Low 
 
 
PCS High 
Hematology 
 
 
WBC 
 2.8x109/L 
 16x109/L 
Neutrophils 
< 1.5 x109/L 
> 13.5 x109/L 
Lymphocytes 
N/A 
> 12.0x109/L 
Monocytes 
N/A 
> 2.5x109/L 
Eosinophils 
N/A 
> 1.6 x109/L 
Basophils 
N/A 
> 1.6 x109/L 
Hemoglobin 
 
Female 
            Male 
 
 95 g/L 
 115 g/L 
 
 175 g/L 
 190 g/L 
Hematocrit 
 
Female 
            Male 
 
 0.32(fraction of 1) 
 0.37(fraction of 1) 
 
 0.54(fraction of 1) 
 0.60(fraction of 1) 
 
RBC 
 3.5 x 1012/L 
 6.4 x 1012/L 
 
Platelet Count 
 75 x 109/L 
 700 x 109/L 
Blood Chemistry 
 
 
Sodium 
 126 mmol/L 
 156 mmol/L 
Potassium 
 3 mmol/L 
 6 mmol/L 
Chloride 
 90 mmol/L 
 118 mmol/L 
Bicarbonate 
 16 mmol/L 
 35 mmol/L 
Calcium 
< 2.05 mmol/L 
 3 mmol/L 
Magnesium 
<0.6 mmol/L 
> 1.15 mmol/L 
Phosphate 
0.65 mmol/L 
1.65 mmol/L 
AST 
N/A 
 3 x ULN 
ALT 
N/A 
 3 x ULN 


 
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Category 
 Parameter Name  
  Gender Restriction, if any 
 
 
PCS Low 
 
 
PCS High 
Alkaline Phosphatase 
N/A 
 3 x ULN 
Creatinine 
N/A 
 177 umol/L 
BUN 
N/A 
 10.71 mmol/L 
Total bilirubin 
N/A 
 34.2 umol/L 
Direct bilirubin 
N/A 
 17.1 umol/L 
Indirect bilirubin 
N/A 
 34.2 umol/L 
Total protein 
 45 g/L 
 100 g/L 
Albumin 
 25 g/L 
N/A 
Uric Acid 
 
Female 
 
Male 
 
N/A 
N/A 
 
 506 umol/L 
 625 umol/L 
Glucose 
2.22 mmol/L 
 9.71 mmol/L 
Urinalysis 
 
 
Ketones 
N/A 
> 4+ 
Glucose 
N/A 
> 4+ 
Thyroid Function 
 
 
Free T4 
< 9.65 pmol/L 
> 22.5 pmol/L 
Free T3 
< 3.07 pmol/L 
> 6.38 pmol/L 
TSH  
0 mIU/L 
> 10 mIU/L