Clinical trial NCT00910247
Conditions: Epilepsy
Keywords: Seizures Epilepsy Anticonvulsant Monotherapy Epilepsy with simple or complete partial onset seizures
Sponsor: Sumitomo Pharma America, Inc.
Start date: 2009-08-01; Completion date: 2017-04-15
Enrollment: 274 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a long term, open-label, safety extension study in subjects with partial onset seizures.

Detailed description:
This is a long term, multicenter, open-label, safety extension study in subjects with partial onset seizures who have just completed, discontinued, or exited the 18-week treatment phase of Protocols 093-045 or 093-046. The initial study duration is 1 year with the option of continuing study drug treatment post 1 year until a subject discontinues study, the study drug becomes clinically available in the subject's locale, or the sponsor terminates the study drug clinical development program.

This study was previously posted by Sepracor Inc. In October 2009, Sepracor Inc. was acquired by Dainippon Sumitomo Pharma., and in October 2010, Sepracor Inc's name was changed to Sunovion Pharmaceuticals Inc.

Arms: arm 1: Open-label treatment with eslicarbazepine acetate will be at doses between 800 and 2400 mg QD
Interventions: intervention 1: Eslicarbazepine acetate
Intervention descriptions: intervention 1: 800 to 2400 mg once daily (QD)

Protocol documents:
Prot_002.pdf: 
  TI
 
 
ESLICARBAZEPINE ACETATE 
STUDY NO. 093-050 
PROTOCOL AMENDMENT HISTORY 
 
LONG-TERM ESLICARBAZEPINE ACETATE EXTENSION STUDY 
 
 
IND No. 67,466 
EudraCT No. 2010-019000-22 
 
15 November 2013 
 
Original Protocol Version 1.0 (24 Sep 2008) 
Amendment No.1, Protocol Version 2.0 (16 Apr 2009) 
Amendment No. 2, Protocol Version 3.0 (24 Jul 2009) 
Non-substantial Amendment No. 1 (22 Apr 2010) 
Amendment No. 3, Protocol Version 4.0 (09 Jun 2010) 
Amendment No. 4, Protocol Version 5.0 (17 Aug 2010) 
Czech Republic–specific Amendment No. 1 (16 Nov 2010) 
Non-substantial Amendment No. 2 (12 Dec 2011) 
Non-substantial Amendment No. 3 (03 Dec 2012) 
Amendment No. 5, Protocol Version 6.0 (07 Jun 2013) 
Non-substantial Amendment No. 4 (15 Nov 2013) 
 


Protocol Amendment History: 093-050 
 
Eslicarbazepine Acetate 
 
Confidential and Proprietary 
2 
15 November 2013 
1. 
SUMMARY OF AMENDMENT HISTORY 
The original protocol (Version 1.0), dated 24 Sep 2008, was globally amended 5 times. There 
was also 1 country-specific amendment for the Czech Republic and 4 non-substantial 
amendments (administrative letters). Brief summaries of the changes are outlined in the sections 
below. 
A country-specific amendment for Russia was also developed; this amendment is not included in 
in this document or the clinical study report as the study was never conducted in Russia. 
 
2. 
AMENDMENT 1, PROTOCOL VERSION 2.0 (16 APRIL 2009) 
FDA feedback received from a Special Protocol Assessment (SPA) request necessitated an 
amendment to Protocol 093-045 version 1.0 (25 July 2008). Based on amended 
Protocol 093-045, version 2.0 (04 March 2009) the following changes were made to the protocol: 
• Throughout the text, new wording “not well controlled by” replaced the previous 
wording  “unresponsive to” so as not to confuse subjects enrolled in the present study 
with patients who have become refractory to other AEDs. 
• Allowance of lorazepam, other benzodiazepines, and newer generation sleep 
medications as occasional sleep medicines (up to once a month). 
• Clarified provision of rescue medication (lorazepam would be provided locally by 
investigator as standard-of-care and not through the sponsor). 
• Addition of testing for creatinine phosphokinase (indicator of muscle lysis caused by 
seizure activity); and elimination of testing for tricyclic antidepressant as part of urine 
drug screen. 
• Addition of diazepam rectal gel dosing chart. 
• Replacement with new versions of medical events calendar, seizure diary, and 
QOLIE-31 scale. 
• Elimination of criteria for independent blinded rater for the MADRS scale (as 
improvement in MADRS was not a primary endpoint of the study and this 
requirement would be better suited for clinical studies of depression. Suicidality 
would be better assessed through the C-SSRS). 
 


Protocol Amendment History: 093-050 
 
Eslicarbazepine Acetate 
 
Confidential and Proprietary 
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15 November 2013 
3. 
AMENDMENT 2, PROTOCOL VERSION 3.0 (24 JULY 2009) 
Protocols 093-045 (Version 2.0, 04 March 2009) and 093-050 (Version 2.0, 16 April 2009) were 
reviewed by Health Canada as part of a CTA application and at an Investigator’s meeting held in 
the USA (3-5 June 2009). Based on feedback received from the regulatory authority and by US 
investigators the following major changes were made to the protocol: 
• Removal of requirement that efficacy and safety assessments must occur in a specific 
order. However, vital signs and ECGs were to be collected prior to blood draws.  
• Further clarification regarding permitted use of benzodiazepines as sleeping 
medications. 
• Addition of dose adjustment requirement for concomitant medications whose plasma 
levels may increase after taper/discontinuation of certain enzyme inducing 
antiepileptic drugs. 
• Allowance of change in setting of vagal nerve stimulator in subjects with a clinically 
significant worsening of seizures or increase in seizure frequency. 
• In cases of subject discontinuation/withdrawal due to need for >2 AEDs, provision of 
instructions that study drug taper schedule would be at Investigator’s discretion and 
an unscheduled visit to record adverse events and return unused study drug. 
• Simplification of seizure diary. 
4. 
NON-SUBSTANTIAL AMENDMENT 1 (22 APRIL 2010) 
The purpose of this non-substantial amendment (administrative letter) was to notify the 
Investigators of the following administrative clarifications to Sepracor Protocol 093-050 
(Version 3.0, 24 July 2009): 
• The EudraCT number for this study is 2010-018684-42. Sites were provided with a 
self-adhesive label citing this EUdraCT number that should have been affixed to the title 
page of the protocol.  
• The telephone and fax numbers for 24-hour SAE Reporting was updated. 
• Section 7.3.3, Health Outcomes Assessments: The site staff could use the review of 
subject entries in the Medical Events Calendar (MEC) as a source to determine if further 
data about the subject’s utilization of health care services should be obtained.  
 


Protocol Amendment History: 093-050 
 
Eslicarbazepine Acetate 
 
Confidential and Proprietary 
4 
15 November 2013 
5. 
AMENDMENT 3, PROTOCOL VERSION 4.0 (09 JUNE 2010) 
Based on continued feedback from the contract research organization and investigative sites 
enrolling subjects the following changes/clarifications were made to the protocol: 
• Addition of information (in table format) on diazepam doses and formulations when 
used as rescue medication in countries where lorazepam as rescue medication was not 
available.  
• Addition of information (in table format) on diazepam doses and formulations when 
used as emergency medication in countries where Diastat® (diazepam rectal gel) as 
emergency medication was not available.  
• Clarification that the Medical Events Calendar (MEC) could have been used as an 
additional tool for collection of health outcomes assessments. 
• Addition of trazodone as allowed medication. 
• Addition of marijuana as a disallowed medication. 
• Clarification that the PI or designee must provide a prescription for diazepam when 
used as emergency or rescue medication (formulation/dose as listed in 
Appendices XII and XIII).  
• Addition of telephone and fax numbers for 24-hour SAE reporting in Europe. 
• Addition of the Eudra CT number. 
• Change in responsible physician. 
• Increase in sample size from 270 to 348 subjects as a result of the increase in sample 
size for Protocols 093-045 and 093-046. 
 


Protocol Amendment History: 093-050 
 
Eslicarbazepine Acetate 
 
Confidential and Proprietary 
5 
15 November 2013 
6. 
AMENDMENT 4, PROTOCOL VERSION 5.0 (17 AUG 2010) 
The sponsor extended the current study duration to beyond 1-year. This allowed subjects who 
demonstrated clinical benefit over a 1-year period to continue receiving study drug beyond 
1-year. There was no change in sample size or change in study drug dosing resulting from the 
extended duration of study. The protocol has been amended to incorporate the following major 
changes:  
• A post-1-year period that would follow the 1-year period. The post-1-year period 
would continue until the subject discontinues study, the study drug becomes clinically 
available in the subject’s locale, or the sponsor terminates the study drug clinical 
development program. 
• Addition of new post-1-year primary objective and 2 new post-1-year secondary 
objectives. 
• Addition of a new post-1-year endpoint. 
• Addition of post-1-year Patient Global Impression (PGI) scale for assessing 
improvement in disease.  
• Addition of a continuation criterion for subjects who choose to continue into the 
post-1-year part of the study. 
 
7. 
CZECH REPUBLIC-SPECIFIC AMENDMENT 1, PROTOCOL 5.1 
(16 NOVEMBER 2010) 
As of October 2010, Sepracor Inc. has changed its name to Sunovion Pharmaceuticals Inc. Edits 
to the protocol were made to reflect the name change.  
8. 
NON-SUBSTANTIAL AMENDMENT 2 (12 DECEMBER 2011) 
The purpose of this letter was to notify the Investigators of the administrative change to 
Sunovion Pharmaceuticals Inc. Protocol 093-050 (Version 5.0, 17 Aug 2010, Czech 
Republic-Specific Local Amendment Version 5.1, 16 Nov 2010, and Russia-specific Protocol 
Version 5.1, 14 Jan 2011). 
The contact for reporting of SAEs, pregnancies, and any other immediately reportable events 
was updated. 


Protocol Amendment History: 093-050 
 
Eslicarbazepine Acetate 
 
Confidential and Proprietary 
6 
15 November 2013 
9. 
NON-SUBSTANTIAL AMENDMENT 3 (03 DECEMBER 2012) 
The purpose of this non-substantial amendment (administrative letter) was to notify the 
Investigators of the following administrative changes to Sunovion Pharmaceuticals Inc. Protocol 
093-050 (Version 5.0, 17 Aug 2010; Czech Republic-specific Local Amendment Version 5.1, 
16 Nov 2010; and Russia-specific Protocol Version 5.1, 14 Jan 2011): 
• For clarification, all pregnancy tests (urine and serum) were to be conducted in female 
subjects of child bearing potential ONLY. The definition of child-bearing potential was 
provided in Section 8.1 (Subject Inclusion/Exclusion Criteria) of the protocol. 
• Effective 03 Dec 2012 serious adverse events, (SAEs), pregnancies, and any other 
immediately reportable events for Protocol 093-050 were to be reported to PPD 
Pharmacovigilance (PVG).  
10. 
AMENDMENT 5, PROTOCOL VERSION 6.0 (07 JUNE 2013)  
The protocol was amended to remove the following post-1-year EOS/ET visit assessments: 
clinical laboratory evaluations (performed only if clinically indicated), coagulation testing, 
thyroid panel, lipid panel, bone turnover markers, and serum pregnancy tests. The post-1-year 
EOS/ET 12-lead ECG assessment was to be performed only if clinically indicated. The Sponsor 
determined that these assessments do not contribute additional information needed to evaluate 
the overall safety profile of eslicarbazepine acetate. 
In addition, updates outlined in non-substantial amendments (administrative letters) sent to the 
sites such as safety reporting information, Medical Monitor contact information, and change in 
company name were also included in this amendment. 
11. 
NON-SUBSTANTIAL AMENDMENT 4 (15 NOVEMBER 2013) 
The purpose of the non-substantial amendment (administrative letter) was to notify the 
Investigators of the following administrative change to Sunovion Pharmaceuticals Inc. Protocol 
093-050 (Version 6.0, dated 07 Jun 2013): 
Sections 11.1 (ECGs); 11.4.9 (End of Study/Early Termination); Appendix III (Cardiac 
Safety Monitoring); and Appendix IX (Computerized Systems Used for Source Data):  A 
post-1-year ECG assessment, if performed, should have been over-read. 
 

Prot_001.pdf: 
1. 
TITLE PAGE 
 
  
 
Protocol No. 093-050 
 
 
 
Long-Term Eslicarbazepine Acetate Extension Study 
 
 
 
IND No. 67,466 
EudraCT No. 2010-019000-22 
 
Final Version 6.0 
Incorporates Amendment No. 5 
07 June 2013 
 
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 proprietary to Sunovion Pharmaceuticals Inc.  This information is being provided to you for 
the purpose of conducting a clinical 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 consistent with that 
stated above. 
 
 


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PROCEDURES IN CASE OF EMERGENCY 
Emergency Contact Information 
Role in Study 
Name 
Address/Telephone Number  
Responsible Physician 
   
Senior Medical Director, Clinical 
Research, CNS 
Sunovion Pharmaceuticals Inc. 
O    
    
F    
Medical Monitor 
(United States; please 
also refer to individual 
site communication 
regarding primary 
Medical Monitor for 
each site) 
    
Director, Medical Affairs 
INC Research 
 
3        
    
T 
F   
G    
Senior Medical Director (back up 
Medical Monitor) 
INC Research 
 
3    
R    
    
    
Medical Monitor 
(Europe) 
 
     
     
    
24-Hour Serious 
Adverse 
Event/Pregnancy 
Reporting 
PPD PVG  
Hotline Number: 919-456-6001 
Fax: 919-654-0211 
Email: 
SunovionSafety@druginfo.com 


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2. 
SYNOPSIS 
Name of Sponsor/Company:  Sunovion Pharmaceuticals Inc. 
Name of Study Drug:  Eslicarbazepine acetate 
Name of Active Ingredient:  Eslicarbazepine acetate 
Title of Study:  Long-Term Eslicarbazepine Acetate Extension Study 
Study Center(s):  Approximately 150 investigative US and ex-US sites are planned to enroll subjects. 
Principal Investigator(s):  To be determined. 
Investigator(s):  To be determined. 
Phase of Development:  III 
Primary Objective:  To evaluate the 1-year and post-1-year safety and tolerability of eslicarbazepine 
acetate flexible dosing within the range of 800 mg to 2400 mg in subjects with partial epilepsy who 
have participated in an 18-week double-blind eslicarbazepine acetate monotherapy study 
(Protocols 093-045 or 093-046). 
Secondary Objectives:   
• 
To evaluate the maintenance of the therapeutic effects of eslicarbazepine acetate over a 
1-year and post-1-year open-label period. 
• 
To evaluate the health-related quality-of-life, suicidality, and depressive symptoms over a 
1-year and post-1-year open-label period. 
Study Design:  The present study is a long-term, multicenter, open-label, safety extension study in 
male and female subjects (aged 16 to 70 years, inclusive) with partial onset seizures who have just 
completed, discontinued, or exited the 18-week treatment phase of Protocols 093-045 or 093-046.  The 
initial study duration is 1-year with the option of continuing study drug treatment post-1-year until a 
subject discontinues study, the study drug becomes clinically available in the subject’s locale, 
or the sponsor terminates the study drug clinical development program. 
This study will evaluate the safety and maintenance of effect of long-term eslicarbazepine acetate 
treatment at flexible doses in the range of 800 mg to 2400 mg once-a-day (QD) over a 1-year and a 
post-1-year period. 
Subjects who enter the present study will receive a starting dose of 1600 mg QD of eslicarbazepine 
acetate, orally for 1 week at the start of the 1-year period.  The starting dose for subjects who had a 
dose reduction during participation in studies 093-045 or 093-046 will be 1200 mg and not 
1600 mg.  At the end of this 1-week period, subjects will be allowed to continue at this dose or at the 
discretion of the Investigator, increase, or decrease dose as necessary for efficacy or tolerability 
reasons.  There is no limit on the number of dose increments or reductions during the study, however, 
all dose increases or reductions should occur in steps of 400 mg and a minimum of 1 week must pass 
between one dose change and the next.  Dose reductions of more than 400 mg are allowed at the 
discretion of the Investigator for a documented safety reason.  The maximum allowed dose of 
eslicarbazepine acetate is 2400 mg QD and the minimum allowed dose is 800 mg QD in this study.  
Subjects who continue into the post-1-year part of the study will continue to receive the same dose of 
study drug that they received at Visit 7 (end of 1-year of treatment).  The same dosing rules as in the 
1-year part of the study are applicable in the post-1-year part. 


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Subjects with a clinically significant increase in seizure frequency, duration, or severity, who have not 
responded to or did not tolerate an increase in dose of study drug, may be started on an additional 
antiepileptic drug (AED) during both the 1-year and post-1-year parts of the study.  A maximum of two 
additional AEDs to control seizures will be allowed, however oxcarbazepine will not be allowed.  If, 
after the addition of the second additional AED, the subject experiences an adverse event, the dose of 
eslicarbazepine acetate should be reduced before changing the dose of the concomitant AED.  In 
addition, for subjects with a vagal nerve stimulator (VNS), the device setting may be changed 
as needed. 
Subjects who require doses outside of the 800 mg QD to 2400 mg QD range or more than 2 additional 
AEDs during the 1-year or post-1-year parts of the study will be discontinued from study participation. 
Physicians may prescribe lorazepam for rescue use.  Diazepam (rectal gel) as an emergency medication 
will be provided by the sponsor (via prescription from local physician).  In countries where lorazepam 
and/or diazepam rectal gel are not available, alternate treatments are allowed per Appendices XII and 
XIII. 
Number of Subjects (Planned):  Up to 348 subjects (up to 174 subjects each from Protocols 093-045 
and 093-046) may be enrolled. 
Diagnosis and Main Criteria for Inclusion:  Subjects with partial onset seizure epilepsy not well 
controlled with one or two AEDs and who have completed, discontinued, or exited from Protocols 
093-045 or 093-046 are eligible to participate.  Subjects who discontinued from Protocols 093-045 or 
093-046 for reasons other than reaching exit criteria may be eligible if there is no safety concern.  
Subjects must have completed at least the first 3 weeks of the 18-week double-blind treatment period 
of these studies to enroll in this study.  Subjects must enter the present study immediately upon 
completion, discontinuation, or exit from Protocols 093-045 or 093-046. 
Study Drug, Dosage and Mode of Administration:  During both the 1-year and post-1-year parts of 
the study, eslicarbazepine acetate, 800 mg, 1200 mg, 1600 mg, 2000 mg, or 2400 mg per day; oral 
administration once daily in the morning with water, with or without food.  Administered as a 
combination of 400 mg tablets of eslicarbazepine acetate.  Subjects receiving 800 mg eslicarbazepine 
acetate per day will receive two 400 mg tablets per day; 1200 mg will receive three 400 mg tablets per 
day; 1600 mg will receive four 400 mg tablets per day; 2000 mg per day will receive five 400 mg 
tablets per day; and 2400 mg will receive six 400 mg tablets per day.  All tablets are to be taken 
simultaneously, when applicable. 
Duration of Treatment:  Total duration of treatment is 1-year and beyond (post-1-year).  Subjects 
may discontinue the study at any time due to worsening of seizures, tolerability, or other reasons. 
Reference Therapy, Dosage, and Mode of Administration:  None. 
Criteria for Evaluation:   
1-Year Safety Endpoints: 
• 
Clinical evaluations (adverse events, vital signs, orthostatic effects, physical examination, body 
weight, and 12-lead electrocardiograms [ECGs]). 
• 
Clinical laboratory evaluations (serum chemistry, hematology and urinalysis), high-density 
lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol, and triglycerides), 
coagulation testing (prothrombin time [PT]/international normalized ratio [INR], and partial 
thromboplastin time [PTT]), bone turnover markers (serum 25-hydroxyvitamin D [25-OHD], 
parathyroid hormone [PTH], osteocalcin, bone-specific alkaline phosphatase, and urinary 


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N-telopeptides of type I collagen cross-links [NTx]). 
• 
Proportion (%) of subjects with increase of body weight ≥7%. 
• 
Proportion (%) of subjects with normal baseline blood sodium reaching levels of 
≤135 mmol/L, ≤130 mmol/L, and ≤125 mmol/L. 
• 
Columbia Suicidality Severity Rating Scale (C-SSRS). 
1-Year Efficacy Endpoints: 
• 
Time on eslicarbazepine acetate monotherapy. 
• 
Seizure frequency reduction from baseline period (Visit 1 to 2) of Protocols 093-045 or 
093-046.  
• 
Responder rate (proportion [%] of subjects with a ≥50% reduction of seizure frequency from 
baseline period [Visit 1 to 2] of Protocols 093-045 or 093-046). 
• 
Proportion (%) of subjects who are seizure-free during the 1-year period (determined in 
12-week intervals). 
• 
Seizure frequency by seizure type. 
• 
Completion rate (proportion [%] of subjects completing the 1-year treatment). 
• 
Treatment retention time (time to withdrawal due to lack of efficacy or adverse events). 
• 
Change in total score from Visit 2 (Day 0) of Protocols 093-045 or 093-046 to end of study 
treatment (Visit 7, Month 12) in 31-Item Quality of Life in Epilepsy (QOLIE-31). 
• 
Change in total score from Visit 2 (Day 0) of Protocols 093-045 or 093-046 to end of study 
treatment (Visit 7, Month 12) in Montgomery-Asberg Depression Rating Scale (MADRS). 
• 
Change in total score from Visit 2 (Day 0) of Protocols 093-045 or 093-046 to end of study 
treatment (Visit 7, Month 12) in MADRS in those subjects with a MADRS score of ≥14 at 
screening visit of the present study. 
Post 1-year Endpoint: 
• 
Fraction of subjects who completed treatment at each visit post-1-year. 
 
Statistical Methods:   
Populations for Analysis:  The intent-to-treat (ITT) population will consist of all subjects who have 
taken any study medication.  The ITT population will be used for safety and efficacy analyses. 
Safety Analysis:  Safety outcomes will be analyzed descriptively.  Safety variables will include adverse 
events, vital sign measurements, orthostatic effects, clinical laboratory evaluations (serum chemistry, 
hematology, and urinalysis), thyroid function, lipid levels, coagulation testing, and bone turnover 
markers, body weight, blood sodium levels, ECG readings, and C-SSRS. 
Efficacy Analysis:  All efficacy endpoints will be summarized descriptively for the treatment group in 
Protocol 093-050.  Time on eslicarbazepine acetate monotherapy will be calculated from the first 
monotherapy dose in 093-045 or 093-046 to the last known dose of eslicarbazepine acetate 
monotherapy in 093-050.  Median time and 95% CI will be estimated using Kaplan Meier time to event 


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methods.  Subjects who were still on eslicarbazepine acetate monotherapy at the end of study will be 
censored at known dose.  Changes in efficacy parameters will be calculated with reference to the 
baseline period of Protocols 093-045 or 093-046. 


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3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF 
FIGURES  
TABLE OF CONTENTS 
1. 
TITLE PAGE ................................................................................................................1 
2. 
SYNOPSIS ...................................................................................................................4 
3. 
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES .................8 
4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................13 
5. 
INTRODUCTION ......................................................................................................15 
6. 
STUDY OBJECTIVES AND PURPOSE ..................................................................17 
6.1. 
Primary Objective .......................................................................................................17 
6.2. 
Secondary Objectives .................................................................................................17 
7. 
INVESTIGATIONAL PLAN .....................................................................................18 
7.1. 
Overall Study Design and Plan ...................................................................................18 
7.2. 
Study Endpoints ..........................................................................................................23 
7.2.1. 
1-Year Safety Endpoints .............................................................................................23 
7.2.2. 
1-Year Efficacy Endpoints .........................................................................................23 
7.2.3. 
Post 1-year Endpoint ...................................................................................................24 
7.3. 
Study Assessments......................................................................................................24 
7.3.1. 
Safety Assessments .....................................................................................................24 
7.3.2. 
Efficacy Assessments .................................................................................................24 
7.3.3. 
Health Outcomes Assessments ...................................................................................25 
8. 
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................26 
8.1. 
Subject Inclusion/Exclusion Criteria ..........................................................................26 
8.2. 
Subject Withdrawal/Discontinuation Criteria .............................................................26 
8.2.1. 
Criterion for Continuation into the Post-1-year Part of Study ....................................27 
9. 
TREATMENT OF SUBJECTS ..................................................................................28 
9.1. 
Concomitant Medications ...........................................................................................28 
9.1.1. 
Disallowed Medications .............................................................................................28 
9.1.2. 
Concomitant Medications Allowed for the Duration of the Study .............................28 
9.2. 
Treatment Compliance ................................................................................................29 
9.3. 
Randomization and Blinding ......................................................................................29 


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9.4. 
Unblinding Procedures ...............................................................................................29 
10. 
STUDY DRUG MATERIALS AND MANAGEMENT ...........................................30 
10.1. 
Description of Study Drug ..........................................................................................30 
10.2. 
Study Drug Packaging and Labeling ..........................................................................30 
10.3. 
Study Drug Storage .....................................................................................................30 
10.4. 
Study Drug Preparation ..............................................................................................30 
10.5. 
Study Drug Administration.........................................................................................31 
10.6. 
Study Drug Accountability .........................................................................................31 
10.7. 
Study Drug Handling and Disposal ............................................................................31 
11. 
TREATMENT PLAN .................................................................................................32 
11.1. 
Standardization of Data Capture .................................................................................32 
11.2. 
Guidelines for MADRS Rater ....................................................................................33 
11.3. 
Electronic Data Capture ..............................................................................................34 
11.4. 
Study Visits .................................................................................................................34 
11.4.1. 
Screening:  Visit 1 (Day 0) .........................................................................................34 
11.4.2. 
Visit 2 (Week 1±1 day) ...............................................................................................35 
11.4.3. 
Visit 3 (Month 1±3 days) ............................................................................................35 
11.4.4. 
Visit 4 (Month 3±1 week) ...........................................................................................36 
11.4.5. 
Visit 5 (Month 6±1 week) ...........................................................................................37 
11.4.6. 
Visit 6 (Month 9±1 week) ...........................................................................................37 
11.4.7. 
Visit 7  (Month 12±1 week) ........................................................................................38 
11.4.8. 
Post-1-year Visit 8 and all Visits onwards (Month 15 and onwards until EOS 
or ET) ..........................................................................................................................39 
11.4.9. 
End of Study/Early Termination .................................................................................39 
12. 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS .............................41 
13. 
ADVERSE EXPERIENCE REPORTING .................................................................42 
13.1. 
Adverse Events ...........................................................................................................42 
13.1.1. 
Objective Findings ......................................................................................................42 
13.1.2. 
Immediately Reportable Events ..................................................................................43 
14. 
STATISTICS ..............................................................................................................45 
14.1. 
General Design ...........................................................................................................45 
14.2. 
Study Endpoints ..........................................................................................................45 
14.3. 
Safety Assessments .....................................................................................................46 


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14.4. 
Efficacy Assessments .................................................................................................46 
14.5. 
Sample Size Determination ........................................................................................46 
14.6. 
Analysis Populations ..................................................................................................46 
14.7. 
Data Analysis ..............................................................................................................46 
14.7.1. 
Subject Disposition and Drug Exposure .....................................................................46 
14.7.2. 
Important Protocol Deviations ....................................................................................47 
14.7.3. 
Demographic and Baseline Characteristics ................................................................47 
14.7.4. 
Safety Analysis ...........................................................................................................47 
14.7.5. 
Adverse Events ...........................................................................................................47 
14.7.6. 
Clinical Laboratory Assessments ...............................................................................48 
14.7.7. 
Electrocardiograms .....................................................................................................48 
14.7.8. 
Vital Signs ..................................................................................................................49 
14.7.9. 
Physical and Neurological Examinations ...................................................................50 
14.7.10. 
Concomitant Medication ............................................................................................50 
14.7.11. 
Columbia-Suicide Severity Tracking Scale ................................................................50 
14.7.12. 
Efficacy Analysis ........................................................................................................50 
15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS.........................................52 
15.1. 
Study Monitoring ........................................................................................................52 
15.2. 
Audits and Inspections ................................................................................................52 
15.3. 
Institutional Review Board .........................................................................................52 
16. 
QUALITY CONTROL AND QUALITY ASSURANCE .........................................53 
17. 
ETHICS ......................................................................................................................54 
17.1. 
Ethics Review .............................................................................................................54 
17.2. 
Ethical Conduct of the Study ......................................................................................54 
17.3. 
Written Informed Consent ..........................................................................................54 
18. 
DATA HANDLING AND RECORDKEEPING .......................................................55 
18.1. 
Computerized Systems ...............................................................................................55 
18.2. 
Inspection of Records .................................................................................................55 
18.3. 
Retention of Records ..................................................................................................55 
19. 
STUDY ACKNOWLEDGMENT ..............................................................................56 
20. 
REFERENCES ...........................................................................................................57 
21. 
APPENDIX I.  ETHICAL AND REGULATORY OBLIGATIONS ........................59 


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21.1. 
Study Conduct ............................................................................................................59 
21.2. 
Institutional Review Board or Independent Ethics Committee ..................................59 
21.3. 
Informed Consent .......................................................................................................60 
21.4. 
Subject Privacy ...........................................................................................................60 
21.5. 
Protocol Amendments and Emergency Deviations ....................................................61 
21.6. 
Monitoring and Auditing of the Study........................................................................61 
21.7. 
Study Documentation .................................................................................................62 
21.8. 
Laboratory Certification and Normal Values .............................................................62 
21.9. 
Drug Accountability ...................................................................................................62 
21.10. 
Records Retention .......................................................................................................63 
21.11. 
Inspection of Records .................................................................................................63 
21.12. 
Financial Disclosure ...................................................................................................63 
22. 
APPENDIX II. CLINICAL LABORATORY TESTS ...............................................64 
23. 
APPENDIX III.  CARDIAC SAFETY MONITORING/ECG...................................66 
24. 
APPENDIX IV.   DEFINITIONS FOR REPORTING ADVERSE EVENTS ..........68 
25. 
APPENDIX V.  STRUCTURED INTERVIEW GUIDE FOR THE 
MONTGOMERY-ASBERG DEPRESSION RATING SCALE (MADRS) 
(SIGMA) .....................................................................................................................69 
26. 
APPENDIX VI.  31-ITEM QUALITY OF LIFE IN EPILEPSY SCALE 
(QOLIE-31) ................................................................................................................75 
27. 
APPENDIX VII.  COLUMBIA-SUICIDE SEVERITY RATING SCALE 
(C-SSRS) ....................................................................................................................82 
28. 
APPENDIX VIII.  MEDICAL EVENT CALENDAR ...............................................92 
29. 
APPENDIX IX.  COMPUTERIZED SYSTEMS USED FOR SOURCE 
DATA .........................................................................................................................94 
30. 
APPENDIX X. SEIZURE DIARY.............................................................................95 
31. 
APPENDIX XI. DIASTAT® (DIAZEPAM RECTAL GEL) DOSING 
CHART .......................................................................................................................97 
32. 
APPENDIX XII. DESCRIPTION OF TREATMENT OPTIONS IN 
COUNTRIES WHERE LORAZEPAM AS RESCUE MEDICATION IS 
NOT AVAILABLE ....................................................................................................98 
33. 
APPENDIX XIII.  DESCRIPTION OF TREATMENT OPTIONS IN 
COUNTRIES WHERE DIASTAT® (DIAZEPAM RECTAL GEL) AS 
EMERGENCY MEDICATION IS NOT AVAILABLE ...........................................99 
34. 
APPENDIX XIV.  PATIENT GLOBAL IMPRESSION (PGI) SCALE .................100 
 


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LIST OF TABLES 
Table 7.1-1:  Schedule of Assessments..........................................................................................21 
 
 
 
 
LIST OF FIGURES 
Figure 7.1-1: Study Schematic ....................................................................................................20 
 


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4. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation 
Full Form 
AE 
Adverse experience/event 
AED 
Antiepileptic drug 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
CNS 
Central nervous system 
eCRF 
Electronic case report form 
CRO 
Contract research organization 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
CV 
Coefficient of Variation 
ECG 
Electrocardiogram 
EOS 
End of study 
ET 
Early termination 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
HDL 
High-density lipoprotein 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee  
IND 
Investigational New Drug 
INR 
International normalized ratio 
IPD 
Important protocol deviation 
IRB 
Institutional Review Board 
ITT 
Intent-to-treat 
LDL 
Low-density lipoprotein 
MAOI 
Monoamine oxidase inhibitor 
MADRS 
Montgomery-Asberg Depression Scale 
MEC 
Medical Event Calendar 
MedDRA 
Medical Dictionary for Regulatory Activities 
µg 
Microgram 
NTx 
N-Telopeptides of type I collagen cross-links 
25-OHD 
25-Hydroxyvitamin D 
OTC 
Over-the-counter 
PR 
Time between P wave and QRS in electrocardiography 
PT 
Prothrombin time 
PTH 
Parathyroid hormone 
PTT 
Partial thromboplastin time 
QD 
Once-a-day 
QOLIE-31 
31-Item Quality of Life in Epilepsy 


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Abbreviation 
Full Form 
QT 
Electrocardiographic interval from the beginning of the 
QRS complex to the end of the T wave 
QTc 
QT interval corrected for heart rate   
SAE 
Serious adverse experience/event 
SOC 
System organ class 
TEAE 
Treatment-emergent adverse event 
TSH 
Thyroid stimulating hormone 
VGSC 
Voltage-gated sodium channel 
® 
Registered trademark (registered in United States Patent 
and Trademark Office) 
 
For the purposes of standardization, the following definitions will be used:   
 
• Screened Subject:  Any subject who signed the study specific informed consent and 
completed at least one study related procedure. 
• Screen Failure Subject:  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 did not achieve on-study status. 
• Study Drug (or study medication):  Term to cover investigational drug 
(eslicarbazepine acetate).  Eslicarbazepine acetate is also referred to as SEP-0002093 
or BIA 2-093 in other related documents.  The study drug will be described as 
eslicarbazepine acetate in this document. 
• Active Treatment Phase:  The period of the study in which the study drug is 
administered. 
• On-Study Subject:  Any subject who passed screening and received study drug; 
and/or had significant procedures as defined by the protocol (eg, biopsy, genetic 
profiling).  Note:  Significant procedures may require subjects to be considered 
on-study as these procedures may drive scheduling of interim monitoring visits and 
management of electronic Case Report Forms (eCRFs). 
• Completed Subject:  Any subject who participated throughout the duration of the 
study, up to and including the last in-clinic visit. 
• Early Termination Subject:  Any subject who was successfully screened and achieved 
on-study status, but did not complete the study. 


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5. 
INTRODUCTION 
Epilepsy is a brain disorder resulting from dysfunction in neuronal signaling and physically 
manifested foremost as seizures.  Illness, head trauma and environmental and genetic factors 
contribute to the etiology of epilepsy.  The disorder affects all age groups, may be chronic and in 
most cases requires long-term therapy. 
The prevalence of epilepsy worldwide is estimated to be approximately 50 million with a 
worldwide incidence rate of 50 to 100 per 100,000 people.1  In the United States (US) more than 
2 million people have active epilepsy.2  About 25% to 30% of these patients have intractable 
epilepsy that does not respond to conventional antiepileptic drug (AED) treatments.2  
Eslicarbazepine acetate, (S)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide, is 
structurally similar to two currently marketed AEDs, carbamazepine and oxcarbazepine.  
However, a key molecular difference at the 10, 11 position of eslicarbazepine acetate confers on 
it a unique metabolic pathway absent of epoxide formation and autoinduction that may 
contribute to side effects observed with the above mentioned AEDs. 
Physiologically, eslicarbazepine acetate is a voltage-gated sodium channel (VGSC) blocker.  The 
VGSCs are transmembrane proteins found in neurons of the central nervous system (CNS) and 
responsible for the conduction of electrical impulses from neuron to neuron.  Deactivation of 
VGSC is associated with altered states of neuronal excitability and has therapeutic advantage in 
treating disorders such as epilepsy.3-5  Genetic mutations in certain VGSC isoforms have been 
linked to development of epilepsy.6-8 
Approximately 1700 subjects have been exposed to eslicarbazepine acetate in 22 Phase I, 
5 Phase II, and 3 Phase III completed clinical studies.  These studies have included healthy 
volunteers, adult and pediatric subjects with partial onset epilepsy, and adults with bipolar 
disorder.  Total daily doses of eslicarbazepine acetate ranged from between 20 mg to 3600 mg in 
adults and 5 to 30 mg/kg/day in children given as single or multiple doses from 1 day to up to 
1 year.  The longest exposure to eslicarbazepine acetate is approximately 38 months as add-on 
therapy in epileptic subjects in an open-label Phase 3 extension study.  The maximum tolerated 
multiple oral dose of eslicarbazepine acetate in healthy adult subjects was 2400 mg QD. 
Three Phase III placebo-controlled clinical studies have been conducted using eslicarbazepine 
acetate as adjunctive therapy in 1,050 randomized adult subjects with partial onset seizures 
refractory to treatment with 1 to 3 concomitant AEDs.  Doses of 800 and 1200 mg/day 
significantly reduced (p<0.0001) the number of seizures compared to placebo over a 12-week 
maintenance period in all studies.  In one open-label long-term extension study (Part II of BIAL 
Studies SCO/BIA-2093-301) adjunctive eslicarbazepine acetate therapy was shown to reduce 
seizures and was well tolerated over a one-year period. 
In April 2009 the Committee for Medicinal Products for Human Use (CHMP) approved 
Zebinix (eslicarbazepine acetate) 400 mg, 600 mg, 800 mg, tablets as adjunctive therapy in 
adults with partial-onset seizures with or without secondary generalization.  The applicant for 
this medicinal product was BIAL - Portela & Ca,S.A. 
 


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The results with eslicarbazepine acetate as adjunctive treatment to other AEDs suggest that the 
compound may be efficacious and well tolerated when administered as a monotherapy and that 
these effects may be sustained over a one-year period.  Clinical experience with oxcarbazepine (a 
sodium channel blocker structurally similar to eslicarbazepine acetate) has shown that higher 
doses of oxcarbazepine can be tolerated as monotherapy than in combination with other AEDs.  
These findings resulted in an approved dose range for oxcarbazepine up to 1200 mg as 
adjunctive therapy, but up to 2400 mg as a monotherapy.9-13  Doses of eslicarbazepine acetate up 
to 2400 mg were well tolerated as monotherapy in patients with bipolar disorder (unpublished 
results). 
Subjects who participated in the double-blind 18-week withdrawal to monotherapy studies 
(Protocols 093-045 and 093-046) with eslicarbazepine acetate will be eligible to participate in 
this long-term extension study.  This study will determine if the efficacy and safety of 
eslicarbazepine acetate monotherapy is sustained over a one-year period. 
The present study design has carefully considered possible long-term risks and benefits for the 
participating subjects.  In cases where subjects experience an increase in seizure severity or 
frequency, an increase in the dose of study drug (in 400 mg increments of up to a maximum of 
2400 mg QD) is allowed.  After the attempt to increase the dose of study drug, the addition of up 
to two AEDs will be allowed to control seizures.  Furthermore, in subjects who do not tolerate 
the assigned dose there will be the possibility of dose reductions (in 400 mg steps) to a minimum 
of 800 mg QD.  If, after the addition of the second AED, the subject experiences an adverse 
event, the dose of eslicarbazepine acetate should be reduced before changing the dose of the 
concomitant AED. 
The available data with eslicarbazepine acetate show that the drug has potential advantages.14,15  
The QD administration may lead to increased convenience for subjects and improved compliance 
with treatment.  Furthermore, the drug shows little or no enzyme induction, no toxic metabolites, 
less sedation or hyponatremia, and does not lead to weight gain so that switching from other 
AEDs to eslicarbazepine acetate may be beneficial for the study participants.   
Long-term data from one study demonstrate the maintenance of effect and safety over the course 
of one year (Part II of BIAL Study SCO/BIA-2093-301).  A total of 314 subjects received 
approximately 880 mg QD (median 800 mg) of eslicarbazepine acetate for 6 to 12 months in this 
study.  Subjects showed significant improvements from baseline in health-related quality of life 
and depressive symptoms.  The most frequent treatment-emergent adverse events (TEAE) 
reported in this study were headache, dizziness, diplopia, and nasopharyngitis (5 to 10%).  
Eleven subjects (3.5%) reported a TEAE that led to discontinuation. 
Eslicarbazepine acetate is also referred to as SEP-0002093 and BIA 2-093 in other related 
documents.  In this document, the term eslicarbazepine acetate will be used to describe the study 
drug.  Please refer to the current Investigator’s Brochure for additional information. 


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6. 
STUDY OBJECTIVES AND PURPOSE 
This study will confirm the long-term safety and maintenance of effect of eslicarbazepine acetate 
(flexible dose range of 800 mg to 2400 mg) in subjects with partial onset seizures, with or 
without secondary generalization, not well controlled by current AEDs. 
6.1. 
Primary Objective 
To evaluate the 1-year and post-1-year safety and tolerability of eslicarbazepine acetate flexible 
dosing within the range of 800 mg to 2400 mg in subjects with partial epilepsy who have 
participated in an 18-week double-blind eslicarbazepine acetate study (Protocols 093-045 or 
093-046). 
6.2. 
Secondary Objectives 
• 
To evaluate the maintenance of the therapeutic effects of eslicarbazepine acetate over a 
1-year and post-1-year open-label period. 
• 
To evaluate the health-related quality of life, suicidality, and depressive symptoms over a 
1-year and post-1-year open-label period. 
 
 


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7. 
INVESTIGATIONAL PLAN 
7.1. 
Overall Study Design and Plan 
The present study is a long-term, multicenter, open-label, safety extension study in male and 
female subjects (aged 16 to 70 years, inclusive) with partial onset seizures who have just 
completed, discontinued, or exited the 18-week treatment phase of Protocols 093-045 or 
093-046.  The initial study duration is 1-year with the option of continuing study drug treatment 
post-1-year until a subject discontinues study, the study drug becomes clinically available in the 
subject’s locale, or the sponsor terminates the study drug clinical development program. 
This study will evaluate the safety and maintenance of effect of long-term eslicarbazepine 
acetate treatment at flexible doses in the range of 800 mg to 2400 mg QD over a 1-year and a 
post-1-year period. 
Subjects who exit Protocols 093-045 or 093-046 by meeting any of the protocol-defined exit 
criteria are eligible to participate in this study.  Subjects who discontinue from Protocols 093-045 
or 093-046 for reasons other than reaching exit criteria may be eligible if there is no safety 
concern.  Subjects must have completed at least the first 3 weeks of the 18-week double-blind 
treatment period of these studies.  Subjects must enter the present study immediately upon 
completion, discontinuation, or exit from Protocols 093-045 or 093-046. 
Subjects who enter the present study will receive a starting dose of 1600 mg QD of 
eslicarbazepine acetate, orally for 1 week at the start of the 1-year period.  The starting dose for 
subjects who had a dose reduction during participation in studies 093-045 or 093-046 will 
be 1200 mg and not 1600 mg.  At the end of this 1-week period, subjects will be allowed to 
continue at this dose or, at the discretion of the Investigator, increase or decrease dose as 
necessary for efficacy or tolerability reasons.  There is no limit on the number of dose increments 
or reductions during the study, however, all dose increases or reductions should occur in steps of 
400 mg and a minimum of 1 week must pass between one dose change and the next.  Dose 
reductions of more than 400 mg are allowed at the discretion of the Investigator for a 
documented safety reason.  The maximum allowed dose of eslicarbazepine acetate is 2400 mg 
QD and the minimum allowed dose is 800 mg QD in this study.  Subjects who continue into the 
post-1-year part of the study will continue to receive the same dose of study drug that they 
received at Visit 7.  The same dosing rules as in the 1-year part of the study are applicable in the 
post-1-year part. 
Subjects with a clinically significant worsening of seizures or increase in seizure frequency, who 
have not responded to or did not tolerate an increase in dose of study drug, may be started on an 
additional AED during both the 1-year and post-1-year parts of the study.  A maximum of two 
additional AEDs to control seizures will be allowed.  However, one of these additional AEDs 
must not be oxcarbazepine.  If, after the addition of the second AED, the subject experiences an 
adverse event, the dose of eslicarbazepine acetate should be reduced before changing the dose of 
the concomitant AED.  In addition, for subjects with a vagal nerve stimulator (VNS), the device 
setting may be changed as needed. 


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Subjects who require doses outside of the 800 mg QD to 2400 mg QD range or more than 
2 additional AEDs during the 1-year or post-1-year parts of the study will be discontinued from 
study participation.  See Figure 7.1-1 for a study schematic.  
Physicians may prescribe lorazepam for rescue use.  Diazepam rectal gel (Diastat®1 [see 
Appendix XI for dosing information]) as an emergency medication will be provided by the 
sponsor (via prescription from local physician).  In countries where lorazepam and/or diazepam 
rectal gel are not available, alternate treatments are allowed per Appendices XII and XIII. 
 
Study Periods 
1-Year Part 
Visit 1 (Screening):  At the end of the 18-week treatment period or early termination from 
Protocols 093-045 or 093-046, subjects who choose to enter this study will undergo procedures 
as outlined in the Schedule of Assessments (Table 7.1-1).  This visit corresponds to Visit 9 (End 
of Treatment/Early Termination Visit) in Protocols 093-045 or 093-046.  Visit 9 assessments 
from Protocols 093-045 or 093-046 will serve as the baseline assessments for the present study at 
Visit 1.  Subjects will receive a starting dose of 1600 mg QD of eslicarbazepine acetate 
(1200 mg QD for subjects who had a dose reduction in Protocols 093-045 or 093-046). 
Visit 2 (Week 1):  Subjects will return to the clinic 1 week after Visit 1 for procedures as 
specified in the Schedule of Assessments (Table 7.1-1).  From this visit onwards, the dose of 
eslicarbazepine acetate may be increased or decreased at the discretion of the Investigator.  There 
is no limit on the number of dose increments or reductions during the study, however, an 
increase or decrease in dose should occur in steps of 400 mg.  Dose reductions of more than 
400 mg are allowed at the discretion of the Investigator for a documented safety reason.  A 
minimum of 1 week must pass between one dose change and the next. 
Visits 3 through 6:  Subjects will return to the clinic after Visit 2 at 3-week (Visit 3), 2-month 
(Visit 4), and 3-month intervals (Visits 5 and 6) for procedures as specified in the Schedule of 
Assessments (Table 7.1-1). 
Visit 7: Subjects will return to the clinic at the end of the 1-year treatment period (3 months after 
Visit 6 [Visit 7]) for procedures as specified in the Schedule of Assessments (Table 7.1-1).  At 
this visit subjects may choose to continue treatment with study drug post-1-year.  Subjects, who 
choose to continue study drug post-1-year, will start this part of the study on the same dose of 
study drug as they received at Visit 7.  Subjects who choose not to continue into the post-1-year 
part of the study will return after 1-week of this visit for EOS/ET procedures (see below). 
Post-1-Year Part 
Visit 8 and onwards (Month 15 onwards):  In the post-1-year part of the study subjects will 
return to the clinic at 3-month intervals for procedures as specified in the Schedule of 
Assessments (Table 7.1-1).  Subjects will continue treatment with study drug until the subject 
discontinues study, the study drug becomes clinically available in the subject’s locale, or the 
sponsor terminates the study drug clinical development program. 
 
1 Reg. US Pat. & Tm. Off. 


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End of Study (EOS)/ Early Termination (ET) Visit:  Subjects will return to the clinic upon 
conclusion of the study (study drug becomes clinically available in the subject’s locale or the 
sponsor terminates the study drug clinical development program) or early termination for 
procedures as specified in the Schedule of Assessments (Table 7.1-1). 
 
Figure 7.1-1: Study Schematic 
 
        V1*    V2(W1)   V3(M1)      V4(M3)          V5(M6)           V6(M9)          V7(M12)      V8(M15)       EOS/ET 
1 
week 
 
 
 
 
 
 
 
Post-1-year 
1600 
mg** 
3 weeks 
2 months 
3 months 
3 months 
3 months 
3 months 
Visits to 
occur every 
3-months 
           
                                                 Flexible dosing 800-2400 mg QD 
 
             
        
        
 
   
  SCN (Day 0)                                                                                                                   
 
EOS=end of study; ET=early termination; M=month; V=visit.                     
*Corresponds to Visit 9 in Protocols 093-045 and 093-046. **1200 mg QD for subjects who had a dose reduction while 
participating in Protocols 093-045 or 093-046.


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Table 7.1-1:  Schedule of Assessments 
Procedures 
Visit 1/ 
SCNa 
Visit 2 
Visit 3 
Visit 4 
Visits 5 and 
6 
Visit 7 
Post-1-year 
Visit 8 
onwards  
EOS/ET 
Computer 
Systemsc 
Day 0 
Week 1 
Month 1 
Month 3 
Months 6 
and 9 
Month 12 
Month 15 
onwardsb 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
X 
 
 
 
 
 
 
 
A 
Physical Examination 
•d 
 
 
 
 
 
 
X 
A 
Neurological Examination 
• 
 
 
 
 
 
 
X 
A 
Vital Sign Measurements  
• 
X 
X 
X 
X 
X 
X 
X 
A 
Height 
• 
 
 
 
 
 
 
X 
A 
Weighte 
• 
X 
X 
X 
X 
X 
X 
X 
A 
Clinical Laboratory Evaluation (Serum 
Chemistry, Hematology, and Urinalysis)f 
• 
 
X 
X 
X 
X 
 
Xg,h 
B 
Coagulation Testing (PT/INR, PTT) 
• 
 
X 
X 
X 
X 
 
Xg 
B 
Thyroid Panel (T3, T4, and TSH) 
• 
 
X 
X 
X 
X 
 
Xg 
B 
Lipid Panel (total cholesterol, 
HDL-cholesterol, LDL-cholesterol, and 
triglycerides)f 
• 
 
X 
X 
X 
X 
 
Xg 
B 
Bone Turnover Markersi 
• 
 
 
 
Xj 
X 
 
Xg 
B 
Serum Pregnancy Testk 
• 
 
X 
X 
X 
X 
 
Xg 
B 
Urine Pregnancy Testk 
 
 
 
 
 
 
X 
X 
 
Urine Drug Screen (Central Lab) 
• 
 
 
 
 
 
 
 
B 
12-Lead ECG 
• 
 
X 
X 
X 
X 
 
Xh 
C 
MADRS 
• 
 
 
 
Xj 
X 
Xl 
X 
A 
QOLIE-31m 
• 
 
 
 
Xj 
X 
Xl 
X 
A 
PGI Scale 
 
 
 
 
 
 
X 
Xn 
 
C-SSRSo 
• 
X 
X 
X 
X 
X 
X 
X 
A 
Health Outcomes Assessments 
• 
X 
X 
X 
X 
X 
X 
X 
A 
Adverse Events 
• 
X 
X 
X 
X 
X 
X 
X 
A 
Concomitant Medications 
• 
X 
X 
X 
X 
X 
X 
X 
A 
Dispense Seizure Diary 
X 
X 
X 
X 
X 
 
 
 
 
Document Seizures in Seizure Diary 
 
X 
X 
X 
X 
 
 
 
A 
Seizure Diary Review 
 
X 
X 
X 
X 
X 
 
Xg 
 
Dispense Study Drug 
X 
X 
X 
X 
X 
Xp 
X 
 
A 


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Table 7.1-1:  Schedule of Assessments 
Procedures 
Visit 1/ 
SCNa 
Visit 2 
Visit 3 
Visit 4 
Visits 5 and 
6 
Visit 7 
Post-1-year 
Visit 8 
onwards  
EOS/ET 
Computer 
Systemsc 
Day 0 
Week 1 
Month 1 
Month 3 
Months 6 
and 9 
Month 12 
Month 15 
onwardsb 
Dispense Emergency Medication 
X 
 
 
 
 
 
 
 
 
Drug Accountability 
 
X 
X 
X 
X 
X 
X 
X 
A 
Dispense/Review MEC 
X 
X 
X 
X 
X 
X 
X 
X 
 
Abbreviations:  A=Electronic Data Capture (Inform); B=Laboratory Information Management System (LIMS); C=Core Lab Over-Read; C-SSRS=Columbia 
Suicidality Severity Rating Scale; EOS=End of Study; ET=Early Termination; MADRS=Montgomery-Asberg Depression Rating Scale; NTx=N-telopeptides of 
type I collagen cross-links; SCN=Screening; 25-OHD=25-hydroxyvitamin D; TSH=thyroid stimulating hormone; PGI=Patient Global Impression; 
PTH=parathyroid hormone; QOLIE-31=31-Item Quality of Life in Epilepsy. 
a. 
Demographic information, medical history, psychiatric history, medication history, magnetic resonance imaging/computerized tomography scans, 
electroencephalogram data, HLA-B*1502 genotyping, and Hepatitis B/C screen results collected during the screening visit of Protocols 093-045 or 093-046 
will apply for this study as well. 
b. Clinic visits to occur at intervals of 3 months during the post-1-year part. 
c. 
Letters in this column identify the computerized systems that will be used in this protocol (Appendix IX). 
d. The symbol “•” represents procedures performed at Visit 9 of Protocols 093-045 or 093-046, the results of which will apply to Visit 1 of the present study as 
well.  These procedures do not have to be repeated. 
e. 
In street clothes without shoes and jacket/coat. 
f. 
Fasting labs. 
g. These assessments are not required to be performed if this visit falls in the post-1-year part of the study. 
h. If this visit falls in the post-1-year part of the study, this assessment may be performed only if clinically indicated (per Investigator judgment) eg, as a follow-up 
on a previously noted abnormality. 
i. 
Includes serum 25-OHD, PTH, osteocalcin, bone-specific alkaline phosphatase, and urinary NTx. 
j. 
At Visit 5 only. 
k. In female subjects of child bearing potential only. 
l. 
Every 6 months (ie, Visits 7, 9, 11, 13 etc.). 
m. Only in subjects ≥18 years at time of signing informed consent in Protocols 093-045 or 093-046. 
n. Only for subjects who discontinue study during the post-1-year part of study. 
o. Fill out “since last visit” scale (Appendix VII).  
p. Only for subjects who continue into the post-1-year part of the study. 
 
 


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7.2. 
Study Endpoints 
7.2.1. 
1-Year Safety Endpoints 
1. Clinical evaluations (adverse events, vital signs, orthostatic effects, physical and full 
neurological examination, body weight, and 12-lead ECGs). 
2. Clinical laboratory evaluations (serum chemistry, hematology and urinalysis), 
high-density lipoprotein (HDL)-cholesterol, low density lipoprotein (LDL)-cholesterol, 
and triglycerides), coagulation testing (PT/INR, and PTT), bone turnover markers (serum 
25-hydroxyvitamin D [25-OHD], parathyroid hormone [PTH], osteocalcin, bone-specific 
alkaline phosphatase, and urinary N-telopeptides of type I collagen cross-links [NTx]). 
3. Proportion (%) of subjects with increase of body weight ≥7%. 
4. Proportion (%) of subjects with normal baseline blood sodium reaching levels of 
≤135 mmol/L, ≤130 mmol/L, and ≤125 mmol/L. 
5. Columbia Suicidality Severity Rating Scale (C-SSRS). 
 
7.2.2. 
1-Year Efficacy Endpoints 
1. Time on eslicarbazepine acetate monotherapy. 
2. Seizure frequency reduction from baseline period (Visit 1 to 2) of Protocols 093-045 or 
093-046.  
3. Responder rate (proportion [%] of subjects with a ≥50% reduction of seizure frequency 
from baseline period [Visit 1 to 2] of Protocols 093-045 or 093-046). 
4. Proportion (%) of subjects who are seizure-free during 1-year period (determined in 
12-week intervals). 
5. Seizure frequency by seizure type. 
6. Completion rate (proportion [%] of subjects completing the 1-year treatment). 
7. Treatment retention time (time to withdrawal due to lack of efficacy or adverse events). 
8. Change in total score from Visit 2 (Day 0) of Protocols 093-045 or 093-046 to end of 
study treatment (Visit 7, Month 12) in 31-Item Quality of Life in Epilepsy (QOLIE-31). 
9. Change in total score from Visit 2 (Day 0) of Protocols 093-045 or 093-046 to end of 
study treatment (Visit 7, Month 12) in Montgomery-Asberg Depression Rating Scale 
(MADRS). 
10. Change in total score from Visit 2 (Day 0) of Protocols 093-045 or 093-046 to end of 
study treatment (Visit 7, Month 12) in MADRS in those subjects with a MADRS score of 
≥14 at screening visit of the present study. 
 


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7.2.3. 
Post 1-year Endpoint 
1. Fraction of subjects who completed treatment at each visit post-1-year. 
7.3. 
Study Assessments 
7.3.1. 
Safety Assessments 
1. 12-Lead ECG, physical and full neurological examinations, and orthostatic effects and 
vital signs as specified in the Schedule of Assessment (Table 7.1-1). 
Note:  Not all orthostatic effects qualify as adverse events (AE).  The decision to report 
an orthostatic effect as an AE will be made by the investigator based upon the overall 
clinical picture of the incident.  Orthostatic changes with clinically significant symptoms 
should be recorded as AEs.  See also Sections 13.1.1, Objective Findings and 14.7.8.1, 
Orthostatic Effects.  
2. Clinical laboratory evaluation (serum chemistries, hematology, and urinalysis), thyroid 
panel (T3, T4, and TSH), lipid panel (total cholesterol, HDL-cholesterol, 
LDL-cholesterol, and triglycerides), and coagulation testing (PT/INR, and PTT) as 
specified in the Schedule of Assessment (Table 7.1-1).  Bone turnover markers (serum 
25-OHD, PTH, osteocalcin, bone-specific alkaline phosphatase, and urinary NTx) as 
specified in the Schedule of Assessment (Table 7.1-1). 
3. Body weight as specified in the Schedule of Assessment (Table 7.1-1). 
4. Adverse event monitoring as specified in the Schedule of Assessment (Table 7.1-1). 
5. C-SSRS16 will be completed by the Investigator or Sub-Investigator (or qualified site 
personnel) as specified in the Schedule of Assessment (Table 7.1-1).  The C-SSRS is 
used to determine the presence and severity of suicidality in subjects (Appendix VII). 
 
7.3.2. 
Efficacy Assessments 
Seizure Diary 
Each subject will be instructed to keep a seizure diary (Appendix X) and record information on 
all seizures for the first one-year of the study starting from Visit 1 (Screening) and ending at 
Visit 7 (see Table 7.1-1).  Subjects or caregivers can complete the study diary; however the 
person who maintains the diary should remain the same throughout the study.  Seizure 
occurrences since the previous visit, based on review of the seizure diary, will be recorded by 
date and seizure type on the eCRF. 
Other Efficacy Assessments 
The effect of eslicarbazepine acetate on other aspects of epilepsy will be evaluated by measuring 
the change from baseline of the following scales as specified in the Schedule of Assessment 
(Table 7.1-1):  
1. The Montgomery-Asberg Depression Rating Scale (MADRS)17 will be performed by a 
credentialed and trained MADRS rater (please see Section 11.2, Guidelines for MADRS 


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Rater).  The MADRS measures the severity of a subject’s depressive symptoms 
(Appendix V). 
2. The 31-Item Quality of Life in Epilepsy Scale (QOLIE-31)18 will be subject 
self-administered.  Subjects will be given sufficient time to complete this questionnaire 
(Appendix VI).  The QOLIE-31 will be administered only in subjects who have 
completed 18 years of age at time of signing informed consent in Protocols 093-045 or 
093-046. 
3. The Patient Global Impression (PGI) scale will be subject self-administered at all visits 
during the post-1-year period only.  The scale measures the patient impression of 
improvement in disease (Appendix XIV). 
7.3.3. 
Health Outcomes Assessments 
Data on utilization of health care services which are not study protocol driven will be collected.  
An assessment of health care resource use for seizure-related care will be performed.  The 
assessment will be performed for exploratory purposes to inform future study designs, generate 
additional study hypotheses, and to provide initial inputs for the development of a health 
economic predictive model.  These data will be collected as specified in the Schedule of 
Assessments (Table 7.1-1).  The site staff may use the review of subject entries in the Medical 
Events Calendar (MEC) as a source to determine if further data about the subject’s utilization of 
health care services should be obtained.  
Results of the health outcomes analysis will be described in a separate report other than the 
clinical study report.  


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8. 
Selection and Withdrawal of Subjects 
8.1. 
Subject Inclusion/Exclusion Criteria 
1. Subject who completed, exited, or discontinued for reasons other than safety from the 
18-week treatment phase of Protocols 093-045 or 093-046 and are willing to continue 
participation in this study are eligible.  Subject must have completed at least the first 
3 weeks of the 18-week double-blind treatment period of Protocols 093-045 or 093-046 
to be eligible. 
2. Subject must give written informed consent prior to participation in the study.  For 
subjects <18 years of age, the informed consent must be signed by the subject’s parent or 
legal guardian, and, when appropriate and/or required by state or local law, minor 
subjects must give written informed assent prior to participation in the study.  All 
subjects must sign privacy authorization form, if applicable.  All females of child bearing 
potential (≤65 years of age) must also sign the “Women of Childbearing Potential” 
Addendum. 
3. Subjects must, in the opinion of the Investigator (with consultation with Medical Monitor 
as appropriate), continue to potentially benefit from continued study participation and 
have no new medical conditions that would preclude study participation. 
4. If female subject, must continue the accepted method of birth control defined in 
Protocols 093-045 or 093-046 for the duration of this study as well. 
 
8.2. 
Subject Withdrawal/Discontinuation Criteria  
1. Subject with serum sodium level ≤125 mmol/L. 
2. Subject with any kind of hypersensitivity (especially manifested as rash) suspected to be 
induced by eslicarbazepine, carbamazepine, oxcarbazepine, or chemically-related 
substances. 
3. Subject who needs to initiate prohibited concomitant medications. 
4. Subject who needs to reduce eslicarbazepine acetate dose to <800 mg QD or increase 
dose to >2400 mg QD. 
5. Subject who needs to use >2 additional AEDs.  If applicable, provide sufficient study 
drug to taper subject off of study drug (taper schedule is at the Investigator’s discretion).  
Schedule a follow-up (unscheduled) visit, if applicable, to assess AEs and to collect all 
remaining study drug in the original container (including any empty containers). 
Please also refer to Section 12, Discontinuation and Replacement of Subjects. 
 


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8.2.1. 
Criterion for Continuation into the Post-1-year Part of Study 
For subjects to continue into the post-1-year part of the study, subjects must, in the opinion of the 
Investigator (with consultation with Medical Monitor, appropriate), continue to potentially 
benefit from continued study participation and have no new medical conditions that would 
preclude study participation. 
 
   


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9. 
TREATMENT OF SUBJECTS 
9.1. 
Concomitant Medications 
9.1.1. 
Disallowed Medications 
The following medications are not allowed in the study:  
• Oxcarbazepine 
• The following CNS medications are not allowed: 
− Antipsychotics; 
− Tricyclic antidepressants; 
− Anxiolytics (including benzodiazepines with exception of rescue and 
emergency medication as listed in Appendices XII and XIII);  
− Sedative hypnotics including non-benzodiazepines (see exceptions below, 
Section 9.1.2);  
− Central opioid agonists/antagonists;  
− Monoamine oxidase inhibitors (MAOIs); 
− Marijuana; 
− Initiation of any treatment with amphetamines. 
 
9.1.2. 
Concomitant Medications Allowed for the Duration of the Study 
• Stable use of selective serotonin reuptake inhibitors (SSRIs) or serotonin 
norepinephrine reuptake inhibitors (SNRIs). 
- Trazodone is allowed during study. 
• Occasional use of rescue medication (no more than once every 28 days) as described 
in Appendix XII. 
• Occasional use of lorazepam or other benzodiazepine as sleeping medication (no 
more than once every 28 days). 
• Occasional use of newer generation non-benzodiazepine sleep medications 
(zolpidem, eszopiclone, ramelteon, or zaleplon) (maximum of once per week). 
• Occasional use of OTC sleep medications (eg, diphenhydramine, melatonin, or herbal 
preparation) (maximum of twice per week). 
• Emergency medication (as described in Appendix XIII). 
• Concomitant medications (eg, drugs like theophylline, coumadin, etc.) whose plasma 
dose levels may significantly change after withdrawal or addition of enzyme inducing 


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AEDs (such as carbamazepine or phenytoin) during the study should be properly 
monitored and their dose adjusted as indicated. 
Hormonal contraceptives are allowed if the subject is on a stable dose for at least 30 days prior to 
Visit 1 and agrees to continue such use throughout the duration of the study and for 30 days after 
the final dose of study drug.  All females on oral contraceptives and hormonal therapy should be 
encouraged to dose at the same time of day each day while on study. 
Chronic medications taken concomitantly during the preceding double-blind study are allowed 
(dose adjustments may be made as needed).  Other treatments may be initiated as medically 
needed except with medications listed in Section 9.1.1 in which case the subject should be 
discontinued from the study. 
Administration of eslicarbazepine acetate 1200 mg QD to female subjects in a previous clinical 
study showed a decrease in systemic exposure to both hormones of a combined oral 
contraceptive containing levonorgestrel and ethinyloestradiol, most likely caused by an induction 
of CYP3A4 in vivo.  Therefore, it must be taken into account that concomitant use of 
eslicarbazepine acetate and hormonal contraceptives may render these contraceptives ineffective. 
Subjects using implanted, injectable, or hormonal contraceptives therefore, must use additional 
methods of contraception for the duration of the study. 
 
9.2. 
Treatment Compliance 
Each subject’s treatment compliance with administration of study drug will be assessed by 
interview and counting the number of returned study drug tablets.  Subjects will be instructed to 
return all unused study drug and empty packaging at each visit. 
 
9.3. 
Randomization and Blinding 
Not applicable. 
 
9.4. 
Unblinding Procedures 
Not applicable.  


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10. 
STUDY DRUG MATERIALS AND MANAGEMENT 
10.1. 
Description of Study Drug  
The study drug will be provided as 400 mg tablets of eslicarbazepine acetate 
[(S)-10-acetoxy-10,11-dihydro-5H-dibenz/b,f/azepine-5-carboxamide].  Subjects will be 
instructed to take tablets at the same time once daily in the morning. 
 
10.2. 
Study Drug Packaging and Labeling 
Subjects will be dispensed multiple 100-count HDPE (plastic) tamper-evident sealed bottles 
containing 100 tablets each per assigned dosing.  All packaging for study drug will be labeled 
with: 
• Protocol number 
• Sponsor’s name and address 
• Local Country Caution Statement 
• Instructions for use and storage 
• Container number(s) to be entered into the eCRF 
• Blank space for Site No. 
• Blank Space for Subject No. 
• Blank Space for Visit No. 
• Blank Space for Investigator name 
• EudraCT Number  
• Lot/Batch Number 
• Expiry  
• Storage Conditions 
 
10.3. 
Study Drug Storage 
Eslicarbazepine acetate should be kept out of the reach and sight of children.  It should be stored 
at controlled room temperature 20°C to 25°C (68°F to 77°F); excursions permitted from 15°C to 
30°C (59°F to 86°F). 
 
10.4. 
Study Drug Preparation 
Not applicable. 


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10.5. 
Study Drug Administration 
Study drug will be supplied as 400 mg tablets of eslicarbazepine acetate.  Subjects will be 
required to take their study drug once every day in the morning with water, with or without food, 
at approximately the same time every day. 
• 
Subjects receiving 800 mg eslicarbazepine acetate per day will take two 400 mg 
tablets per day. 
• 
Subjects receiving 1200 mg eslicarbazepine acetate per day will take three 400 mg 
tablets per day. 
• 
Subjects receiving 1600 mg eslicarbazepine acetate per day will take four 400 mg 
tablets per day. 
• 
Subjects receiving 2000 mg eslicarbazepine acetate per day will take five 400 mg 
tablets per day. 
• 
Subjects receiving 2400 mg eslicarbazepine acetate per day will take six 400 mg 
tablets per day. 
All tablets are to be taken simultaneously, when applicable. 
In countries where available, subjects will be provided with lorazepam (2 mg sublingual) for 
rescue use and diazepam rectal gel (2.5 mg, 2-pack diazepam; Diastat®) for emergency 
medication use.  In countries where lorazepam and/or diazepam rectal gel are not available 
please refer to Appendices XII and XIII for alternate treatments for rescue and emergency use. 
 
10.6. 
Study Drug Accountability 
The Investigator is responsible for storing the study drug in a secure location and for maintaining 
adequate records of drug disposition that includes the dates, quantity, and use by subjects.  If the 
study is terminated, discontinued, suspended, or completed, all unused supplies of study drug 
will be returned to Sunovion Pharmaceuticals Inc. or designee, unless other instructions are 
provided in writing by Contract Research Organization (CRO)/Sponsor.  A drug inventory 
record will be supplied.  The Investigator on an ongoing basis must maintain a drug inventory 
record of supplied, received, dispensed, and returned medication. 
The study drug will not be dispensed to any person who is not a study subject under this 
protocol. 
 
10.7. 
Study Drug Handling and Disposal  
The Investigator is required to return all unused study drug to the Sponsor or designee as 
instructed.  The Investigator is required to maintain copies of medication shipping receipts, drug 
accountability records, and records of return or final disposal of study drug. 
 


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11. 
TREATMENT PLAN 
11.1. 
Standardization of Data Capture 
Study Schematic (Figure 7.1-1) and Schedule of Assessments (Table 7.1-1):  Figure 7.1-1 and 
Table 7.1-1 provide a summary of the study design and the procedures to be conducted at each 
visit. 
Clinic Visits:  Clinic visits should be scheduled in the morning when subjects are required to 
come in a fasting state. 
Assessment Windows:  Assessments will be conducted as specified in Section 11, Treatment 
Plan.  Vital signs and ECGs should be collected prior to blood draws.  All times are relative to 
the time when individual subjects arrive for their clinic visit. 
Vital Signs:  Vital signs will be collected at all clinical visits.  For each visit, vital signs 
following ≥5 minutes rest, consisting of supine systolic and diastolic blood pressures, respiration 
rate, heart rate, and oral body temperature will be measured.  Blood pressure (BP) and heart rate 
(HR) should first be taken with the subject in the supine position after resting for ≥5 minutes.  
Blood pressure and heart 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 heart rate throughout the 
study.  If a subject develops symptoms consistent with orthostatic hypotension (light-headedness, 
dizziness, or changes in sensorium upon standing) at any point, his or her supine and standing 
blood pressure and heart rate should be collected at that time in the manner described above.  
Vital signs will be obtained after ECG and prior to clinical laboratory collection.  Subject’s 
respiration rate and body temperature will also be collected as part of vital sign measurement.  
Height will be measured at Visits 1 and EOS/ET visit only.  Weight will be measured at all 
clinical visits. 
Electrocardiograms:  ECGs will be performed as outlined in the Schedule of Assessments, 
Table 7.1-1. The post-1-year EOS/ET visit ECG is to be collected only if clinically indicated (as 
judged by the Investigator) eg, as follow-up on a previously noted abnormality. .  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 vital sign measurements and drawing blood samples.  All ECGs (except for the post-
1-year EOS/ET ECG, if performed) will be centrally read at a core lab according to established 
quality assurance procedures for inter/intra reader variability.  See Appendix III, Cardiac Safety 
Monitoring/ECG for collection guidelines. 
Clinical Laboratory Evaluation:  All clinical laboratory evaluations required by the protocol 
are outlined in Appendix II (Clinical Laboratory Tests).  All clinical laboratory evaluations are to 
be collected in the fasting state.  For detailed instructions regarding laboratory procedures, 
sampling, and shipping guidelines refer to the Central Laboratory Instructions Manual.  Blood 
samples will be collected at as outlined in the Schedule of Assessments, Table 7.1-1 and 
processed at a central laboratory to ensure consistency.  All laboratories will be College of 
American Pathologists (CAP) and Clinical Laboratory Improvement Amendments (CLIA) (or 
equivalent) certified. 


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Seizure Diary:  All subjects will be given a seizure diary (Appendix X) at Visits 1 through 6 to 
be completed throughout their time on study.  Subjects or caregivers can complete the seizure 
diary; however the person who maintains the diary should remain the same throughout the study.  
Subjects will record information on their seizures in the seizure diary by date and type.  At each 
return visit (Visits 2 through 6), the seizure diary will be reviewed, collected, and a new seizure 
diary will be dispensed.  At Visit 7, the seizure diary will be reviewed and collected only.  A new 
one will not be dispensed. 
Medical Events Calendar:  All subjects will be given a medical events calendar (MEC, 
Appendix VIII) as specified in the Schedule of Assessment (Table 7.1-1) to be completed 
throughout their time on study.  Subjects will record changes in health status or medications in 
the MEC.  At each return visit, the MEC will be reviewed, collected, and a new MEC will be 
dispensed.  At the EOS/ET visit, the MEC will be reviewed and collected only.   
Adverse Events:  Using the MEC as a discussion guide, 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?”). 
Concomitant Medications:  Subject self-report will be acceptable for listing all concomitant 
medication use and evaluation for inclusion/exclusion (Visit 1) except where specific protocol 
procedures are mandated to ensure appropriate enrollment (eg, certain baseline lab values). 
Rating Scales:  The MADRS will be administered by a credentialed and trained MADRS rater 
(see Section 11.2) as specified in the Schedule of Assessments (Table 7.1-1) (Appendix V).  The 
rater shall be asked to avoid inquiring about or evaluating AEs.  The C-SSRS will be 
administered by a trained Investigator or Sub-Investigator (or qualified site personnel) as 
specified in the Schedule of Assessments (Table 7.1-1) (Appendix VII).  The QOLIE-31 is 
subject self-administered and will be administered as specified in the Schedule of Assessments 
(Table 7.1-1) (Appendix VI).  The PGI scale will be subject self-administered during all visits in 
the post-1-year part of the study. 
 
11.2. 
Guidelines for MADRS Rater 
The MADRS must be administered via the Structured Interview Guide for the MADRS 
(SIGMA) by a credentialed and trained MADRS rater who is a qualified clinician.  The scoring 
must be based upon symptom severity assessed/personally observed by the MADRS rater at the 
time of the structured interview.  Assessments must be based entirely upon information gained 
from the interview without any input from third parties or other efficacy or safety assessments.  
Furthermore, interviews by the MADRS rater must be limited to discussion of depression-related 
symptoms measured by this scale and absolutely must avoid discussion of ancillary topics (eg, 
AEs). 
The SIGMA was developed to standardize the manner of administration of the MADRS scale.  
Ratings should be based on the subject’s condition over the prior 7 days. 
At all post-baseline interviews, assessments must be made entirely upon information gained at 
the interview with the subject without reference to other test results. 


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11.3. 
Electronic Data Capture 
The study sites will use a validated electronic data capture (EDC) system to enter subject data 
onto electronic case report forms (eCRFs).  The Inform EDC system through Quintiles will be 
used for this clinical study.  Password protected access to the EDC system will be via a secure 
website.  Data clarification forms and data corrections will be handled through the same system.  
All transactions within the EDC system are fully documented within an electronic audit trail.  
Each set of completed electronic case report forms must be reviewed and electronically signed 
and dated by the Investigator.  In compliance with remote data retention requirements, the study 
sites will be provided with a CD-ROM containing the eCRFs and the complete audit trail in PDF 
format, subsequent to database lock. 
 
11.4. 
Study Visits 
Subjects should be instructed to fast overnight (minimum 8 hours) before each scheduled 
in-clinic visit for which blood samples are to be collected. 
 
11.4.1. 
Screening:  Visit 1 (Day 0) 
Subjects will be evaluated at the Screening Visit to determine their eligibility to enroll in the 
study.  Visit 1 of this study corresponds to Visit 9 of Protocols 093-045 and 093-046.  The 
following procedures are also performed at Visit 9 of Protocols 093-045 and 093-046 and 
therefore do not have to be duplicated in the present study.  The results of the following 
Visit 9 procedures will apply to this study as well. 
• 
 Obtain information on adverse events (AEs) and concomitant medication. 
• Administer the MADRS, QOLIE-31, and C-SSRS. 
• Perform Health Outcomes assessments based upon entries in the MEC and discussion 
with the subject during the visit. 
• Perform a physical examination, including a full neurological examination. 
• Perform a standard 12-lead ECG with 10-second rhythm strip. 
• Obtain vital signs including height and weight. 
• Obtain blood and urine samples for clinical laboratory evaluation (serum chemistry, 
hematology, and urinalysis), coagulation testing, thyroid panel, lipid panel, bone turnover 
markers, serum pregnancy test (female subjects of child bearing potential only), and urine 
drug screen (central lab). 
• Issue the seizure diary and instruct subject on its use. 
• Issue MEC and instruct the subject on its use. 
The following procedures are specific to the present study and are to be performed at Screening: 


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• Obtain signed informed consent (including women of child-bearing potential addendum, 
if applicable) and privacy authorization from the subject before conducting any other visit 
procedures.  Obtain informed assent for subjects <18 years and signed informed consent 
from the parent or legal guardian. 
• Assess inclusion/exclusion criteria. 
• Dispense study drug. 
• Schedule Visit 2 to occur in 1 week and instruct the subject to bring the seizure diary and 
the MEC to Visit 2.  Remind subject to come to next scheduled clinic visit (Visit 2) in a 
fasting state. 
The PI or designee must confirm the subject has a valid prescription for rescue and emergency 
medication or that medication is still available from participation in the double-blind study 
(Protocol 093-045 or 093-046), as applicable (see Appendices XII and XIII) at the screening visit 
so that the subject will have the medication at Visit 2.  For sites in the United States, the PI may 
fax the prescription to the central pharmacy at least 10 days before the expected screening visit.  
For sites in Canada, the prescription should be provided to the subject and the subject asked to 
fill the prescription before returning to the site for Visit 2. 
 
11.4.2. 
Visit 2 (Week 1±1 day) 
The following study-related procedures will be performed at Visit 2. 
• Collect and review the seizure diary and MEC.  Record changes in concomitant 
medications, including over-the-counter (OTC) and health and dietary supplements, and 
AEs that may have occurred between Visit 1 and Visit 2. 
• Administer the C-SSRS scale. 
• Perform Health Outcomes assessments based upon entries in the MEC and discussion 
with the subject during the visit. 
• Obtain vital signs including weight. 
• Dispense study drug. 
• Perform drug accountability. 
• Re-dispense the seizure diary and MEC. 
• Schedule Visit 3 to occur after 3 weeks of Visit 2.  Remind subject to bring all remaining 
Visit 2 study drug in the original container (including any empty containers), seizure 
diary, and the MEC to the next scheduled visit.  Remind subject to come to next 
scheduled visit in a fasting state. 
 
11.4.3. 
Visit 3 (Month 1±3 days)  
The following assessments will be conducted at the Month 1 visit (Visit 3): 


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• Collect and review the seizure diary and MEC.  Record changes in concomitant 
medications, including OTC and health and dietary supplements, and AEs that may have 
occurred between Visit 2 and Visit 3. 
• Administer the C-SSRS scale. 
• Perform Health Outcomes assessments based upon entries in the MEC and discussion 
with the subject during the visit. 
• Perform a standard 12-lead ECG with 10-second rhythm strip. 
• Obtain vital signs including weight. 
• Obtain blood samples for clinical laboratory evaluation (serum chemistry, hematology, 
and urinalysis), coagulation testing, thyroid panel, lipid panel, and serum pregnancy test 
(female subjects of child bearing potential only). 
• Dispense study drug. 
• Perform drug accountability. 
• Re-dispense the seizure diary and MEC. 
• Schedule Visit 4 to occur within 2 months after Visit 3.  Remind subject to bring all 
remaining Visit 3 study drug in the original container (including any empty containers), 
seizure diary, and the MEC to the next scheduled visit.  Remind subject to come to next 
scheduled clinic visit in a fasting state. 
 
11.4.4. 
Visit 4 (Month 3±1 week) 
The following assessments will be conducted at the Month 3 visit (Visit 4): 
• 
Collect and review the seizure diary and MEC.  Record changes in concomitant 
medications, including OTC and health and dietary supplements, and AEs that may have 
occurred between Visit 3 and Visit 4. 
• 
Administer the C-SSRS scale. 
• 
Perform Health Outcomes assessments based upon entries in the MEC and discussion 
with the subject during the visit. 
• 
Perform a standard 12-lead ECG with 10-second rhythm strip. 
• 
Obtain vital signs including weight. 
• 
Obtain blood samples for clinical laboratory evaluation (serum chemistry, hematology, 
and urinalysis), coagulation testing, thyroid panel, lipid panel, and serum pregnancy test 
(female subjects of child bearing potential only). 
• 
Dispense study drug. 
• 
Perform drug accountability. 
• 
Re-dispense the seizure diary and MEC. 


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• 
Schedule Visit 5 to occur within 3 months after Visit 4.  Remind subject to bring all 
remaining Visit 4 study drug in the original container (including any empty containers), 
seizure diary, and the MEC to the next scheduled visit.  Remind subject to come to next 
scheduled clinic visit in a fasting state. 
 
11.4.5. 
Visit 5 (Month 6±1 week) 
The following assessments will be conducted at the Month 6 visit (Visit 5): 
• Collect and review the seizure diary and MEC.  Record changes in concomitant 
medications, including OTC and health and dietary supplements, and AEs that may have 
occurred between Visit 4 and Visit 5. 
• Administer the MADRS, QOLIE-31, and C-SSRS scales.  
• Perform Health Outcomes assessments based upon entries in the MEC and discussion 
with the subject during the visit. 
• Perform a standard 12-lead ECG with 10-second rhythm strip. 
• Obtain vital signs including weight. 
• Obtain blood samples for clinical laboratory evaluation (serum chemistry, hematology, 
and urinalysis), coagulation testing, thyroid panel, lipid panel, bone turnover markers, 
and serum pregnancy test (female subjects of child bearing potential only). 
• Dispense study drug. 
• Perform drug accountability. 
• Re-dispense the seizure diary and MEC. 
• Schedule Visit 6 to occur 3 months after Visit 5.  Remind subject to bring all remaining 
Visit 5 study drug in the original container (including any empty containers), seizure 
diary, and the MEC to the next scheduled visit.  Remind subject to come to next 
scheduled clinic visit in a fasting state. 
 
11.4.6. 
Visit 6 (Month 9±1 week) 
The following assessments will be conducted at the Month 9 visit (Visit 6): 
• Collect and review the seizure diary and MEC.  Record changes in concomitant 
medications, including OTC and health and dietary supplements, and AEs that may have 
occurred between Visit 5 and Visit 6. 
• Administer the C-SSRS scale. 
• Perform Health Outcomes assessments based upon entries in the MEC and discussion 
with the subject during the visit. 
• Perform a standard 12-lead ECG with 10-second rhythm strip. 


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• Obtain vital signs including weight. 
• Obtain blood samples for clinical laboratory evaluation (serum chemistry, hematology, 
and urinalysis), coagulation testing, thyroid panel, lipid panel, and serum pregnancy test 
(female subjects of child bearing potential only). 
• Dispense study drug. 
• Perform drug accountability. 
• Re-dispense the seizure diary and MEC. 
• Schedule Visit 7 to occur within 3 months after Visit 6.  Remind subject to bring all 
remaining Visit 6 study drug in the original container (including any empty containers), 
seizure diary, and the MEC to the next scheduled visit.  Remind subject to come to next 
scheduled visit in a fasting state. 
 
11.4.7. 
Visit 7  (Month 12±1 week) 
The following assessments will be conducted at the Month 12 visit (Visit 7): 
• Collect and review the seizure diary and MEC.  Record changes in concomitant 
medications, including OTC and health and dietary supplements, and AEs that may have 
occurred between visit 6 and Visit 7. 
• Administer the MADRS, QOLIE-31, and C-SSRS scales. 
• Perform Health Outcomes assessments based upon entries in the MEC and discussion 
with the subject during the visit. 
• Perform a standard 12-lead ECG with 10-second rhythm strip. 
• Obtain vital signs including weight. 
• Obtain blood samples for clinical laboratory evaluation (serum chemistry, hematology, 
and urinalysis), coagulation testing, thyroid panel, lipid panel, bone turnover markers, 
and serum pregnancy test (female subjects of child bearing potential only). 
• Perform drug accountability. 
• Ask subject to choose if wants to continue receiving study drug and continue into the 
post-1-year part of the study. 
- Subjects who choose not to continue into the post-1-year part of the study, this 
visit is considered as the EOS visit and additional procedures (eg, physical 
examination, neurological examination, urine pregnancy test [female subjects of 
child bearing potential only], and height) as specified in Section 11.4.9 are to be 
followed. 
- If subject continues into the post-1-year part of the study: 
1. 
Schedule Visit 8 to occur within 3 months after Visit 7. 
2. 
Dispense study drug and MEC. 


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3. 
Remind subject to bring all remaining Visit 7 study drug in the original 
container (including any empty containers), and the MEC to the next 
scheduled visit. 
11.4.8. 
Post-1-year Visit 8 and all Visits onwards (Month 15 and onwards until EOS or 
ET) 
Subjects who choose to continue into the post-1-year part of the study will visit the clinic at 
3-month intervals until EOS or ET (see Section 11.4.9).  At each post-1-year visit, the following 
assessments will be conducted: 
• Collect and review the MEC.  Record changes in concomitant medications, including 
OTC and health and dietary supplements, and AEs that may have occurred between this 
visit and the last clinical visit. 
• Administer the C-SSRS scale. 
• Administer the MADRS and QOLIE-31 scales (only at alternate visits [coinciding with 
6-month intervals from Visit 7 ie, Visits 7, 9, 11, 13 etc]). 
• Administer the PGI scale. 
• Perform Health Outcomes assessments based upon entries in the MEC and discussion 
with the subject during the visit. 
• Obtain vital signs including weight. 
• Obtain urine sample for urine pregnancy test (female subjects of child bearing potential 
only). 
• Dispense study drug. 
• Perform drug accountability. 
• Re-dispense the MEC. 
• Schedule the next visit to occur within 3 months of this visit.  Remind subject to bring all 
remaining previous visit study drug in the original container (including any empty 
containers), and the MEC to the next scheduled visit. 
 
11.4.9. 
End of Study/Early Termination  
The following assessments will be conducted for the EOS/ET Visit: 
• Collect and review the seizure diary (for subjects who discontinue in the 1-year part of 
study only) and MEC.  Record changes in concomitant medications, including OTC and 
health and dietary supplements, and AEs that may have occurred since last visit. 
• Administer the MADRS, QOLIE-31, and C-SSRS scales.  
• Administer the PGI scale (only for subjects who continued in to the post-1-year period of 
the study). 


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• Perform Health Outcomes assessments based upon entries in the MEC and discussion 
with the subject during the visit. 
• Perform a physical examination, including a full neurological examination. 
• Perform a standard 12-lead ECG with 10-second rhythm strip (for subjects who 
discontinue in the post-1-year part of study, this assessment is to be performed only if 
clinically indicated [per Investigator judgement] eg, as follow-up on a previously noted 
abnormality. A post-1-year ECG assessment, if performed, is not to be overread). 
• Obtain vital signs including weight and height. 
• Obtain blood samples for clinical laboratory evaluation (serum chemistry, hematology, 
and urinalysis), coagulation testing, thyroid panel, lipid panel, bone turnover markers, 
and serum and urine pregnancy test (female subjects of child bearing potential only). For 
subjects who discontinue in the post-1-year part of study, only the urine pregnancy test 
(in female subjects of child bearing potential only) is to be performed. Serum chemistry, 
hematology, and urinalysis to be performed only if clinically indicated (per Investigator 
judgement) eg, as follow-up on a previously noted abnormality. 
• Perform drug accountability. 
• Ask subject to initiate other AEDs (if applicable). 
• If applicable for early termination or discontinued subjects, provide sufficient study drug 
to taper the subject off of study drug as needed (taper schedule is at the Investigator’s 
discretion). 
• If applicable, schedule a follow-up (unscheduled) visit to assess AEs and to collect all 
remaining study drug in the original container (including any empty containers). 


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12. 
DISCONTINUATION AND REPLACEMENT OF SUBJECTS 
Subjects in this clinical study may be discontinued for any of the following reasons: 
• Adverse event 
• Protocol violation 
• Withdrawal of consent 
• Lost to follow-up 
• Physician decision 
• Other  
Every effort should be made for all subjects prematurely discontinuing from the study, regardless 
of cause, to undergo final evaluation procedures, in accordance with Section 11.4.9, Early 
Termination Visit. 
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 that is not consistent with protocol 
participation, (eg, violates inclusion/exclusion criteria), the subject must be discontinued. 
Subjects whose study participation is prematurely terminated will not be replaced. 
Please also see Section 8.2, Subject Withdrawal/Discontinuation Criteria. 
 
 


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13. 
ADVERSE EXPERIENCE REPORTING 
13.1. 
Adverse Events  
An AE is any reaction, side effect or other undesirable event that occurs in conjunction with the 
use of the study drug, whether or not the event is considered drug-related. 
Adverse events will be collected from the time the informed consent is signed to the end of the 
study.  Serious adverse events (SAEs) will be collected and reported on the SAE form, from the 
time of informed consent to 30 days post–last-dose and will be followed until resolution or lost 
to follow-up.  SAEs occurring from the time of informed consent to the end of study must be 
recorded on the eCRF and the data recorded should match that on the SAE form. 
Non-leading questions will be used to ask subjects about the possible occurrence of 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. 
Following questioning and evaluation, all AEs, whether believed by the Investigator to be related 
or unrelated to the study drug, must be documented in the subject’s study records/source 
documents, in accordance with the Investigator’s normal clinical practice, and on the AE page of 
the eCRF.  Each AE is to be evaluated for duration, intensity, seriousness, and causal 
relationship to the study drug.  Appendix IV (Definitions for Reporting Adverse Events) 
provides definitions for severity of an adverse event, relationship to study drug, frequency, and 
action taken.  An AE is deemed associated with the use of the study drug “if there is a reasonable 
possibility that the experience may have been caused by the drug” (21 CFR 312.32 [a]). 
The Medical Monitor is the initial contact person for protocol-related questions or discussion of 
adverse events.  The name and contact information of the Medical Monitor is provided on page 3 
of this protocol. 
 
13.1.1. 
Objective Findings 
New and worsening signs and symptoms of underlying or emerging disease must be recorded as 
adverse events.  Clinically significant abnormal objective findings (eg, clinical laboratory value, 
ECG value, and physical examination observation) will also be recorded on the Adverse Event 
page of the eCRF.  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 adverse event. 
Clinical laboratory test results will be reviewed by an Investigator as they become available.  The 
Investigator must determine the clinical significance of all out of range values and assign a 
deviation code.  Possibly drug-related or clinically relevant abnormal values of uncertain 
causality must be repeated.  Any abnormal values that persist should be followed at the 


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discretion of the Investigator.  Laboratory reports will be initialed and dated on all pages by a 
1572-listed Investigator. 
Abnormal laboratory findings will be rated according to the following scale:  
1 = Deviation from reference range and not clinically significant; not related to 
underlying condition or disease; 
2 = Deviation from reference range and not clinically significant; related to any 
underlying condition or disease; or 
3 = Deviation from reference range and clinically significant (to be followed until 
normalized or new baseline; if post-screening, a corresponding AE must be recorded). 
A positive drug screen does not require a deviation code. 
 
13.1.2. 
Immediately Reportable Events 
There are two categories of medical events that could occur during participation in a clinical 
study that must be immediately reported to PPD Pharmacovigilance (PVG):  
• Serious adverse event (SAE), including death 
• The incidence of pregnancy 
PPD PVG must be contacted immediately upon first knowledge of the incident. 
PPD PVG:  
Hotline Number: (919) 456-6001 
Fax: (919) 654-0211 
Email: SunovionSafety@druginfo.com  
Emergency contact information is also provided on page 3 of this protocol. 
A SAE is any untoward medical occurrence at any dose that results in death, is life-threatening, 
requires hospitalization or prolongation of hospitalization, results in persistent or significant 
disability/incapacity, or is a congenital anomaly/birth defect.  In addition, based on medical and 
scientific judgment, important medical events that do not result in any of the outcomes listed 
above but may jeopardize the subject or require medical or surgical intervention to prevent one 
of the these outcomes, should also usually be considered serious. 
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. 
If an Investigator or study site staff becomes aware of a serious adverse experience that occurs in 
a study subject from the time that informed consent is signed through 30 days following the last 
dose of study drug, this must be reported immediately to PPD PVG. 
In addition to the initial telephone notification, an initial SAE form as applicable must be 
completed and sent via fax to PPD PVG within 1 business day of an Investigator or study site 
staff becoming aware of the event.  Sunovion Pharmaceuticals Inc. provides the SAE form used 


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to report SAEs as a part of the document package necessary to conduct this clinical study.  PPD 
PVG will forward all SAE reports to Sunovion Pharmaceuticals Inc. 
Sunovion Pharmaceuticals Inc. will promptly notify all research sites of an adverse experience 
that is determined to be reportable to the Regulatory Authorities.  These adverse events must be 
promptly reported to the Institutional Review Board (IRB) or Independent Ethics Committee 
(IEC) by the Principal Investigator. 
If a subject becomes pregnant during the course of the study, she will be instructed to 
immediately stop taking study drug.  Further, the subject will be instructed to return within 
48 hours of the first notification of pregnancy to the research site and undergo a serum pregnancy 
test, as confirmation of pregnancy.  If positive, the subject will be immediately discontinued 
from the study and undergo all early study termination procedures.  All pregnancies, whether or 
not the subject received any study drug, 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 facsimile to 
PPD PVG within 1 business day of first knowledge by the research personnel of the pregnancy.  
Sunovion Pharmaceuticals Inc. provides the Pregnancy Event Form as a part of the document 
package necessary to conduct this clinical study.  Pregnancies occurring from the time the 
informed consent is signed through 30 days following the last dose of study drug will be 
followed quarterly until birth or termination of the pregnancy. 


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14. 
STATISTICS 
14.1. 
General Design  
The present study is a 1-year and beyond, multicenter, open-label, flexible dosing safety 
extension study in male and female subjects (aged 16 to 70 years, inclusive) with partial onset 
seizures who have just completed, discontinued, or exited the 18-week treatment phase of 
Protocols 093-045 or 093-046.  The study will evaluate the safety and maintenance of effect of 
long-term eslicarbazepine acetate monotherapy treatment at flexible doses in the range of 
800 mg to 2400 mg per day. 
Subjects who exit Protocols 093-045 or 093-046 by meeting any of the protocol-defined exit 
criteria are eligible to participate in this study.  Subjects who discontinue from Protocols 093-045 
or 093-046 for reasons other than reaching exit criteria may be eligible if there is no safety 
concern.  Subjects must have completed at least the first 3 weeks of the 18-week double-blind 
treatment period of these studies.  Subjects must enter the present study immediately upon 
completion, discontinuation, or exit from Protocols 093-045 or 093-046. 
Subjects who enter the present study will receive a starting dose of 1600 mg QD of 
eslicarbazepine acetate, orally for a period of 1 week.  The starting dose for subjects who had 
a dose reduction during participation in studies 093-045 or 093-046 will be 1200 mg and not 
1600 mg.  At the end of this 1-week period, subjects will be allowed to continue at this dose or at 
the discretion of the Investigator, increase, or decrease dose as necessary for efficacy or 
tolerability reasons.  There is no limit on the number of dose increments or reductions during the 
study, however, all dose increases or reductions should occur in steps of 400 mg and a minimum 
of 1 week must pass between one dose change and the next.  Dose reductions of more than 
400 mg are allowed at the discretion of the Investigator for a documented safety reason.  The 
maximum allowed dose of eslicarbazepine acetate is 2400 mg QD and the minimum allowed 
dose is 800 mg QD in this study. 
Subjects with a clinically significant worsening or increase in seizure frequency, who have not 
responded or did not tolerate an increase in dose of study drug, may be started, at the discretion 
of the investigator on an additional AED.  A maximum of two additional AEDs (excluding 
oxcarbazepine) to control seizures will be allowed.  If, after the addition of the second AED, the 
subject experiences an adverse event, the dose of eslicarbazepine acetate should be reduced 
before changing the dose of the concomitant AED.  In addition, for subjects with a VNS, the 
device setting may be changed as needed. 
Subjects who require doses outside of the 800 mg QD to 2400 mg QD range or more than 2 other 
AEDs will be discontinued from study participation. 
 
14.2. 
Study Endpoints 
The study endpoints are listed in Section 7, Investigational Plan. 
 


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14.3. 
Safety Assessments  
Safety assessments are described in Section 7.3.1, Safety Assessments. 
 
14.4. 
Efficacy Assessments 
Efficacy assessments are described in Section 7.3.2, Efficacy Assessments. 
 
14.5. 
Sample Size Determination 
Subjects will continue on to this study from Protocols 093-045 or 093-046 as of their own 
choosing.  Therefore, the sample size is outside of statistical considerations. 
 
14.6. 
Analysis Populations 
The intent-to-treat (ITT) population will consist of all subjects who have taken any open-label 
study medication.  The ITT population will be used for safety and efficacy analyses. 
 
14.7. 
Data Analysis 
This section specifies data analysis for the first 1-year study period.  Safety and efficacy data 
collected post-1-year period will be summarized descriptively. 
14.7.1. 
Subject Disposition and Drug Exposure 
Subject disposition will be summarized and presented for the number and percentage of subjects, 
who were enrolled, received open-label treatment, completed the study, and discontinued early 
(including reasons for discontinuations).  Percent compliance will be summarized for the 
open-label treatment period.  The number of tablets taken will be derived as the number of 
tablets dispensed minus the sum of the number of tablets returned and the number of tablets 
reported lost.  Percent compliance will be derived as the number of tablets taken divided by the 
number of doses that should have been taken, expressed as a percent.  A listing of drug 
accountability will be presented for all medication distributed to each subject, including number 
of tablets dispensed, returned, lost/stolen, taken, and overall percent compliance. 
The extent of exposure to the open-label medications as well as the number of doses taken will 
be summarized with descriptive statistics and presented.  For each subject, the number of doses 
taken will be computed from the study drug dispensation and accountability eCRF records 
obtained at each visit.  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 for the entire open-label period. 
 


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14.7.2. 
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 during open-label treatment period 
• Developed withdrawal criteria but were not withdrawn 
The potentially important protocol deviations will be identified shortly before database lock, 
either programmatically (eg, inclusion/exclusion criteria violations) or through review of data 
listings (eg, investigator comments, concomitant medications).  Appropriate personnel 
(including, at a minimum, a medical director, and a biostatistician) will review the list of 
potential IPDs to identify which will be considered IPDs.  The final list of IPDs will be 
documented and used to generate a data listing.  The number and percentage of subjects with 
IPDs will be summarized by the categories above. 
 
14.7.3. 
Demographic and Baseline Characteristics 
Demographic and baseline characteristics, including age, gender, race (where applicable), height, 
weight, and BMI, as well as disease conditions, will be summarized using descriptive statistics. 
 
14.7.4. 
Safety Analysis 
Safety outcomes will be analyzed descriptively.  Safety variables will include adverse events, 
vital sign measurements, orthostatic effects, clinical laboratory evaluations (serum chemistry, 
hematology, and urinalysis), thyroid function, lipid levels, coagulation testing, and bone turnover 
markers, body weight, blood sodium levels, ECG readings, and C-SSRS. 
 
14.7.5. 
Adverse Events 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA), 
Version 11.0 or higher.  Treatment-emergent adverse events (TEAEs) will be defined as:   
• AEs that occurred on or after the first dose of study drug,  
• AEs with a missing start date and a stop date on or after the first dose of study drug, or 
• AEs with both a missing start and stop date.  
TEAEs will be summarized by MedDRA system organ class (SOC) and Preferred Term (PT) for 
the entire study period, as well as for monotherapy period.  The monotherapy period includes 
time since first monotherapy dose to the time when additional AEDs were added, without regard 
to changes in monotherapy dosage. 
The following TEAEs will be summarized and presented by MedDRA SOC and PT: 


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• All AEs (including number of events and subject incidence) 
• AEs by severity (mild, moderate, severe) 
• AEs by relationship to treatment (unrelated, or potentially 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 preferred term. 
• If a subject reports more than one adverse event within a preferred term and/or a body 
system, the adverse event with the highest known severity within each body system and 
within each preferred term will be included in the summaries by severity. 
• For summaries by relationship to study drug, AEs whose relationship to treatment is 
assessed as “not related” will be grouped as “unrelated.”  Adverse events assessed as 
“unlikely,” “possible,” “probable,” or “definite,” unknown or missing will be grouped as 
“potentially related.”  If a subject reports more than one AE within the same treatment 
regimen, SOC and PT, and any are related, it will be summarized as related. 
A listing of serious AEs, as well as a listing of AEs leading to discontinuation or death, will be 
presented as appropriate. 
 
14.7.6. 
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 
(PCS) 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.  Changes from baseline will be 
calculated from 093-045 or 093-046 baseline data (Visit 2, Day 0). 
 
14.7.6.1. Blood Sodium Levels 
In addition to descriptive summaries of blood sodium levels and changes from baseline for each 
assessment timepoint, the percent of subjects with normal baseline sodium level reaching 
≤135 mmol/L but >130 mmol/L, ≤130 mmol/L but >125 mmol/L, and ≤125 mmol/L will be 
summarized by timepoint and overall postdose. 
 
14.7.7. 
Electrocardiograms 
ECG parameters and changes in these parameters from baseline will be summarized using 
descriptive statistics (number of subjects, mean, standard deviation, median, minimum, and 


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maximum) at each time point.  Changes from baseline will be calculated from 093-045 or 
093-046 baseline data. 
The number and percentage of subjects with QTc-F values in the following categories will be 
summarized: 
• QTc-F >500 ms at any postdose time point not present at baseline 
• QTc-F >450 ms at any postdose time point not present at baseline 
• Change from baseline in QTc-F ≥60 ms for at least 1 postdose measurement 
• Change from baseline in QTc-F ≥30 ms for at least 1 postdose measurement, but 
<60 ms for all postdose measurements 
This categorical analysis will be also performed for QTc-B.  The number and percentage of 
subjects with ECG abnormalities will be presented in the categories of overall, rhythm, 
conduction, morphology, myocardial infarction and the presence of ST, T, and U wave 
abnormalities. 
 
14.7.8. 
Vital Signs 
Vital signs, including systolic and diastolic blood pressure, heart rate, weight, and respiratory 
rate, will be summarized using descriptive statistics at baseline and post open-label treatment 
visits.  Change from baseline (in 093-045 or 093-046) will be included in this presentation as 
well.  In addition, a subject incidence (and percentage) of potentially clinically significant (PCS) 
vital signs values will be presented.  Height at baseline and end of study will be summarized. 
 
14.7.8.1. Orthostatic Effects 
Heart rate and both supine and standing blood pressure will be collected as part of the vital signs 
assessment.  Orthostatic effects will be evaluated by summarizing the number and percentage of 
subjects with a decrease of ≥20 mmHg in standing systolic or ≥10 mmHg in standing diastolic 
blood pressure, as compared to the supine position.  The number and percentage of subjects with 
a heart rate increase of at least 20 beats per minute and heart rate >100 beats per minute after the 
subject was standing for at least 2-4 minutes compared to the heart rate measured in the supine 
position will also be summarized.  Summaries will be presented over time and postdose overall. 
Note:  The categorization of orthostatic effects is intended for the data analysis and reporting of 
group effects and does not constitute guidance as to whether individual assessments 
reflect clinically meaningful changes (see Section 13.1.1, Objective Findings for the protocol 
definition of clinically significant abnormal objective findings). 
 


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14.7.9. 
Physical and Neurological Examinations 
The physical and neurological examinations of subjects at beginning of the study and end of 
study will be summarized by presenting the number and percentage of subjects with normal and 
abnormal findings in each body area (skin/extremities, EENT, head/neck, etc.). 
 
14.7.9.1. Body Weight 
In addition to descriptive summaries of body weight measures and changes from baseline for 
each assessment timepoint, the percent of subjects with increase of body weight ≥7% from 
baseline will be summarized by timepoint and overall postdose. 
 
14.7.10. 
Concomitant Medication 
Other than the study drug, any medication taken by subjects during the course of the study will 
be considered concomitant.  The number and percentage of subjects using each concomitant 
medication will be summarized according to the WHODRUG preferred term.  Subjects with 
multiple uses of a concomitant medication will be counted once for a given PT. 
 
14.7.11. 
Columbia-Suicide Severity Tracking Scale  
The percentage of subjects in each classification class at each assessment time will be 
summarized. 
 
14.7.12. 
Efficacy Analysis 
All efficacy endpoints will be summarized descriptively for the planned treatment received in 
Protocol 093-050.  Changes in efficacy parameters will be calculated with reference to the 
baseline period of Protocols 093-045 or 093-046. 
Time on eslicarbazepine acetate monotherapy will be calculated from the first monotherapy dose 
in 093-045 or 093-046 to the last known dose of eslicarbazepine acetate monotherapy in 
093-050.  Median time and 95% CI will be estimated using Kaplan Meier time to event methods.  
Subjects who were still on eslicarbazepine acetate monotherapy at the end of study will be 
censored at the end of study.  Subjects who dropped out the study while receiving monotherapy 
treatment will be censored at the time of the dropout. Change in dosage levels from 093-045 or 
093-046, dosage changes during 093-050, and the time gap between the parent studies and the 
extension study will be ignored. 
Response rate and seizure frequency reduction will be calculated with reference to the baseline 
period of Protocols 093-045 or 093-046.  Seizure frequency during the 1 year open label period 
and during 3 month visit windows (V1 to V4 as the first 3 month period) will be standardized to 
28 day rate.  The standardized seizure frequency and changes from baseline will be summarized 
overall for the 1-year study period and for each 3 month visit window.  Responder is defined as 
subjects who have ≥50% reduction in standardized seizure frequency over baseline.  The 


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proportion of responders will be summarized by overall study period and by 3 month visit 
window. These analyses will be also conducted by dose level received in 093-045 or 093-046. 
Seizure-free subjects will be computed in every 3-month interval defined above during the study 
period. 
Proportion (%) of subjects seizure-free during study period, and completion rate (proportion [%] 
of subjects completing the one-year treatment) will be provided. 
Standardized seizure frequency will be calculated for each seizure type during the open-label 
period and each 3-month visit window. 
Treatment retention time (time to withdrawal due to lack of efficacy or adverse events) will be 
estimated using KM methods.  The time will be calculated from the first dose of eslicarbazepine 
acetate monotherapy in 093-045 or 093-046 to the last known dose of open-label eslicarbazepine 
acetate in 093-050.  The time may include taking eslicarbazepine acetate concomitantly with 
other AEDs.  Subjects who are still taking eslicarbazepine acetate at the end of study will be 
censored at the end of study. 
Change in total score from Visit 2 (Day 0) of Protocols 093-045 or 093-046 to end of study 
treatment (Visit 7, Month 12) in QOLIE-31 will be summarized. 
The total MADRS score will be summarized descriptively and the change in the total score will 
be summarized.  In addition, change in total score from Visit 2 (Day 0) of Protocols 093-045 or 
093-046 to end of study treatment (Visit 7, Month 12) in MADRS in those subjects with a 
MADRS score of ≥14 at screening visit of the present study. 
 


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15. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
15.1. 
Study Monitoring 
Study monitoring is detailed in Appendix I (see section 21.6). 
 
15.2. 
Audits and Inspections 
The study audit process is detailed in Appendix I (see section 21.6). 
 
15.3. 
Institutional Review Board  
IRB is detailed in Appendix I (see section 21.2). 
 


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16. 
QUALITY CONTROL AND QUALITY ASSURANCE  
Quality control and quality assurance are detailed in Appendix I (see Sections 21.1 and 21.6). 
 


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17. 
ETHICS 
17.1. 
Ethics Review 
17.2. 
Ethical Conduct of the Study 
The Investigator agrees that the study will be conducted according to the protocol, the US Code 
of Federal Regulations, the principles of Good Clinical Practice (GCP), the World Medical 
Association Declaration of Helsinki (1989), and the International Conference on Harmonization 
(ICH) Guidelines.  The Investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws of the pertinent regulatory authorities. 
The Investigator must sign and return to the Sponsor or its representative the "Study 
Acknowledgment" page and provide a copy of a current curriculum vitae, including copy of 
current medical license.  As this study is conducted under an Investigational New Drug (IND), 
the Investigator must sign and return a completed Form United States Food and Drug 
Administration (FDA) 1572 "Statement of Investigator" to the Sponsor or its representative. 
The ethical and regulatory obligations of the Investigator are detailed in Appendix I. 
 
17.3. 
Written Informed Consent 
The informed consent process is detailed in Appendix I (see Section 21.3). 
 


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18. 
DATA HANDLING AND RECORDKEEPING 
18.1. 
Computerized Systems 
A list of the computerized systems that will be used to create, modify, maintain, archive, retrieve, 
or transmit source data are listed in Appendix IX, per the Guidance for Industry Computerized 
Systems Used in Clinical Investigations, May 2007. 
 
18.2. 
Inspection of Records 
The inspection of records is detailed in Appendix I (see Section 21.11). 
 
18.3. 
Retention of Records 
The retention of records is detailed in Appendix I (see Section 21.10). 
 


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19. 
STUDY ACKNOWLEDGMENT 
I have read the foregoing Protocol No. 093-050 “Long-Term Eslicarbazepine Acetate Extension 
Study” Version 6.0, and agree that it contains all necessary details for conducting this 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:  ___________________________________________ 


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20. 
REFERENCES 
1. WHO website www.who.int/mediacentre/factsheets/fs165/en/. 
2. NIH website www.ninds.nih.gov/disorders/epilepsy/detail_epilepsy.htm#113773109. 
3. Perucca E.  The new generation of antiepileptic drugs: advantages and disadvantages. Br 
J Clin Pharamcol.  1996; 42:531-543. 
4. Perucca E, French, J, Bialer, M.  Development of new antiepileptic drugs: challenges, 
incentives, and recent advances.  Lancet Neurology. 2007; 6:793-804. 
5. Tarnawa I, Bölcskei H, Kocsis P. Blockers of voltage-gated sodium channels for the 
treatment of central nervous system diseases. Recent Patents CNS Drug Discov. 2007; 
2:57-78. 
6. Zucca C, Redaelli F, Epifanio R, Zanotta N, Romeo A, Lodi M, Veggiotti P, Airoldi G, 
Panzeri C, Romaniello R, De Polo G, Bonanni P, Cardinali S, Baschirotto C, Martorell L, 
Borgatti R, Bresolin N, Bassi MT.  Cryptogenic epileptic syndromes related to SCN1A: 
twelve novel mutations identified.  Arch Neurol. 2008; 65:489-94. 
7. Xu R, Thomas EA, Gazina EV, Richards KL, Quick M, Wallace RH, Harkin LA, Heron 
SE, Berkovic SF, Scheffer IE, Mulley JC, Petrou S. Generalized epilepsy with febrile 
seizures plus-associated sodium channel beta1 subunit mutations severely reduce beta 
subunit-mediated modulation of sodium channel function. Neuroscience. 
2007;148:164-174. 
8. Sun H, Zhang Y, Liang J, Liu X, Ma X, Qin J, Qi Y, Wu X. Seven novel SCN1A 
mutations in Chinese patients with severe myoclonic epilepsy of infancy.  Epilepsia. 
2008;49:1104-1107. 
9. Sachdeo R, Beydoun A, Schachter S, Vazquez B, Schaul P, Mesenbrink P, Kramer L, 
D’Souza J.  Oxcarbazepine (Trileptal) as a monotherapy in patients with partial seizures. 
Neurology. 2001;57:864-871. 
10. Schachter SC, Vazquez B, Fisher RS, Laxer KD, Montouris GD, Combs-Cantrell DT, 
Faught E, Willmore LJ, Morris GL, Ojemann L, Bennett D, Mesenbrink P, D’Souza J, 
Kramer L.  Oxcarbazepine: double-blind, randomized, placebo-control monotherapy trial 
for partial seizures. Neurology. 1999;52:732-737. 
11. Barcs G, Walker EB, Elger, CE, Scaramelli A, Stefan H, Sturm Y, Moore A, Flesch G, 
Kramer L, D’Souza J.  Oxcarbazepine placebo-controlled, dose-ranging trial in refractory 
partial epilepsy.  Epilepsia. 2000; 41:1597-1607. 
12. Beydoun A, Sachdeo RC, Rosenfeld WE et al. Oxcarbazepine monotherapy for 
partial-onset seizures: a multicenter, double-blind, clinical trial.  Neurology. 2000; 
54:2245-2251. 
13. Trileptal® (Oxcarbazepine) Package Insert. Novartis Pharmaceuticals Corporation, East 
Hanover, NJ. August 2007. 


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14. Almeida L, Soares-da-Silva P. Eslicarbazepine acetate (BIA 2-093). Neurotherapeutics. 
2007;4:88-96. 
15. Elger C, Bialer M, Cramer JA, Maia J, Almeida L, Soares-da-Silva P. Eslicarbazepine 
acetate: A double-blind, add-on, placebo-controlled exploratory trial in adult patients 
with partial-onset seizures.  Epilepsia. 2007;48:497-504. 
16. Posner K, Melvin GA, Stanley B, Oquendo MA, Gould M. Factors in the assessment of 
suicidality in youth.  CNS Spectr.  2007; 12:156–162. 
17. Montgomery SA, Asberg M. A new depression scale designed to be sensitive to change. 
Br J Psychiatry. 1979; 134:382-389. 
18. Cramer, JA, Perrine K, Devinsky O, Bryant-Comstock L, Meador K, Hermann BP.  
Development and cross-cultural translation of a 31-item quality of life questionnaire 
(QOLIE-31).  Epilepsia. 1998; 39:81-88. 


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21. 
APPENDIX I.  ETHICAL AND REGULATORY OBLIGATIONS 
21.1. 
Study Conduct 
The Investigator agrees that the study will be conducted according to the principles of Good 
Clinical Practice (GCP), the World Medical Association Declaration of Helsinki (1989), and ICH 
guidelines.  The Investigator will conduct all aspects of this study in accordance with all 
national, state, and local laws of the pertinent regulatory authorities. 
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 current audits, and will demonstrate due 
diligence in recruiting and screening study subjects. 
The Investigator must sign and return to CRO/Sponsor the "Study Acknowledgment" page and 
provide a copy of current curriculum vitae, including a copy of a current medical license, current 
DEA license, where applicable, and financial disclosure.  In countries where medical licensure is 
not issued, the following documentation is acceptable, as applicable:  
• Registration number/stamp with a registration number stated on curricula vitae (CV) 
• Appropriate diploma number stated on CV 
• Copy of the diploma 
For all studies conducted under an IND, the Investigator must sign and return a completed Form 
FDA 1572 "Statement of Investigator" to CRO/Sponsor. 
 
21.2. 
Institutional Review Board or Independent Ethics Committee 
Before initiation of the study, the Investigator/CRO must obtain approval or favorable opinion of 
the research protocol, informed consent form, and any advertisement for subject recruitment, 
from an IRB or IEC complying with the provisions specified in 21 CFR Part 56 or in ICH GCP, 
as applicable, and applicable pertinent government regulations.  The Investigator must assure 
IRB or IEC compliance with the applicable regulations. 
A copy of written IRB or IEC approval or favorable opinion of the protocol, informed consent 
form and advertising (if applicable) must be provided to CRO/Sponsor prior to initiation of the 
study.  The approval or favorable opinion letter must be signed by the IRB or 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 or IEC complies with the requirements in 21 CFR 
Part 56 for a study conducted under an IND or ICH GCP, as applicable. 
The Investigator/CRO is responsible for obtaining continued review of the clinical research or 
submitting periodic progress reports, in accordance with applicable regulations, at intervals not 
exceeding one year or otherwise specified by the IRB or IEC.  The Sponsor must be supplied 
with written documentation of continued review of the clinical research. 


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The Investigator must promptly inform their IRB/IEC of all SAEs or other safety information 
reported from CRO/Sponsor in accordance with 21 CFR 312.66, or when dictated by applicable 
local regulations (ie Directive 2001/20/EC), the Sponsor/CRO is responsible for reporting to the 
IEC (eg, reporting of serious AEs). 
 
21.3. 
Informed Consent 
The Investigator will prepare the informed consent form and provide the form to CRO/Sponsor 
for approval prior to submission to the IRB or IEC.  CRO/Sponsor may provide a template 
informed consent form to be qualified by each research facility to conform to local requirements.  
All informed consent forms must contain the minimum elements as mandated by the FDA or 
governing regulatory authority and ICH guidelines and will be subject to CRO/Sponsor’ 
approval as well as IRB or IEC approval.  CRO/Sponsor may submit informed consent forms to 
a central IRB or IEC for review and approval or favorable opinion contingent upon prior 
Investigator permission and review. 
Before recruitment and enrollment, each prospective candidate will be given a full explanation of 
the study, allowed to read the approved informed consent form (or assent form for prospective 
candidates <18 years of age) 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 individual (or parent or legal guardian for individuals <18 years of age) understands the 
implications of participating in the study, the subject will be asked to give consent (or assent for 
subjects <18 years of age) to participate in the study by signing the informed consent/assent 
form.  As part of the consent process, each subject mush consent to direct access to his/her 
medical records for study-related monitoring, auditing, IRB/IEC review and regulatory 
inspection.  The Investigator will provide a copy of the signed informed consent form to each 
subject.  For subjects <18 years the parent or legal guardian will be required to provide written 
informed consent. 
If an amendment to the protocol changes the subject participation schedule in scope or activity, 
or increases the potential risk to the subject, the informed consent/assent form must be revised, 
submitted to the IRB or IEC for review and approval or favorable opinion.  The revised informed 
consent/assent form must be used to obtain consent/assent from a subject currently enrolled in 
the study if he or she is affected by the amendment.  The revised informed consent/assent form 
must be used to obtain consent/assent from any new subjects who are enrolled into the study 
after the date of the approval or favorable opinion of the amendment. 
 
21.4. 
Subject Privacy 
The Sponsor’s staff or any designees affirm and uphold the subject’s confidentiality.  
Throughout this study, all data forward to the Sponsor will be identified only by an identification 
number.  The Investigator agrees that its representatives, its designee, representatives of the 
relevant IRB/IEC or representatives of the regulatory authorities will be allowed to review that 
portion of the subject’s primary medical records that directly concerns this study (including, but 
not limited to, clinical laboratory test result reports, ECG reports, admission/discharge 


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summaries for hospital admissions occurring during a subject’s study participation and autopsy 
reports for deaths occurring during the study). 
For the studies conducted in the US, in accordance with the Healthcare Information Portability 
and Accountability Act of 1996, the Investigator will prepare a privacy authorization form and 
provide the form to CRO/Sponsor for approval prior to submission to the IRB/IEC or to a 
Privacy Board.  CRO/Sponsor may provide a template privacy authorization form to be qualified 
by each research facility to conform to local requirements.  The content of the privacy 
authorization form must comply with the regulations governing the authorization.  All 
prospective study candidates will be given full explanation of the privacy authorization form, 
allowed to read the approved form, and be provided the opportunity to ask any questions.  Once 
all questions have been answered and the Investigator is assured that the individual understands 
the implications of the privacy authorization form, the subject will be asked to sign the privacy 
authorization.  The authorization remains in effect until revoked by the subject.  The Investigator 
will provide a copy of the signed privacy authorization form to each subject.  Subjects who do 
not sign the privacy authorization form will not be permitted to participate in the study. 
 
21.5. 
Protocol Amendments and Emergency Deviations 
Changes to the research covered by this protocol must be implemented by formal protocol 
amendment.  Amendments to the protocol may be initiated by the Sponsor or at the request of the 
Investigator.  In either case, a formal amendment cannot be initiated until the Sponsor has 
approved it, the Investigator has signed it off, and it has been reviewed and has received approval 
or favorable opinion by the IRB or IEC. 
Emergency deviations or modifications may be initiated without the Sponsor’s or IRB/IEC 
approval or favorable opinion, only in cases where the change is necessary to eliminate an 
immediate apparent hazard to subjects.  Emergency deviations or modifications must be reported 
to CRO/Sponsor and the IRB/IEC within five business days of the occurrence, or in accordance 
with applicable regulatory requirements. 
 
21.6. 
Monitoring and Auditing of the Study 
A clinical monitor, whether an employee of the Sponsor or its designated representative, has the 
obligation to follow this study closely.  In doing so, the monitor will visit the clinical study sites 
at periodic intervals, in addition to maintaining necessary telephone and letter contact.  The 
monitor will maintain current personal knowledge of the study through observation, review of 
study records and source documentation, and discussion of the conduct of the study with the 
Investigator and staff.  Quality assurance auditors, whether an employee of the Sponsor or its 
designated representative, may evaluate the conduct of the study by the clinical study sites.  
These parties must have access to any and all study reports and source documentation, regardless 
of location and format.  The Sponsor audit reports will be kept highly confidential. 


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21.7. 
Study Documentation 
As part of the responsibilities assumed by participating in the study, the Investigator agrees to 
maintain adequate case histories for the subjects treated as part of the research under this 
protocol.  The Investigator agrees to maintain accurate source documentation and eCRFs as part 
of the case histories. 
Study records are comprised of source documents, eCRFs, 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 documentation is defined as any hand written or computer generated document that 
contains medical information or test results that have been collected for or is in support of the 
protocol specifications, eg, clinical lab reports, clinic notes, drug disbursement log, subject sign 
in sheets, subject completed questionnaires, telephone logs, ECGs, etc.  All draft, preliminary 
and pre final iterations of a final report are also considered to be source documents, eg, faxed lab 
reports and hard copy lab reports, faxed initial results and hard copy, final report. 
The CRO/Sponsor will supply electronic case report forms (eCRFs).  All requested information 
must be entered on the eCRFs.  If an item is not available or is not applicable, this fact should be 
indicated; do not leave a space blank.  Each set of completed eCRFs must be reviewed, 
electronically signed and dated by the Investigator. 
 
21.8. 
Laboratory Certification and Normal Values 
A central laboratory will be used for analysis for most of the clinical labs for this study.  The 
central laboratory will provide the Investigator, CRO and Sponsor with laboratory 
certification(s), a dated copy of normal range values for the central clinical laboratory selected to 
analyze clinical specimens, and the lab director’s CV.  If an exception is granted to use a local 
laboratory, the Investigator must supply the CRO/Sponsor with laboratory certification, lab 
director’s CV and a current, dated copy of normal range values. 
 
21.9. 
Drug Accountability 
The Investigator is responsible for storing the drug in a secure location and for maintaining 
adequate records of drug disposition that includes the dates, quantity, and use by subjects.  If the 
investigation is terminated, discontinued, suspended or completed, all unused supplies of drug 
will be returned to the Sponsor, unless other instructions are provided in writing by 
CRO/Sponsor. 
The drug will not be dispensed to any person who is not a study subject under this protocol. 
If a drug is subject to the Controlled Substances Act or other similar local regulations, the 
Investigator shall take adequate precautions, including storage of the study drug in a securely 
locked cabinet, or other enclosure, access to which is limited. 
 


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21.10. 
Records Retention 
The Investigator agrees to retain study records for the time periods stated below.  The 
Investigator agrees to contact CRO/Sponsor before destroying any study documentation.  Should 
the Investigator leave the site at which the study was conducted, CRO/Sponsor will be contacted 
regarding the disposition of document storage. 
Records will be retained until at least 2 years after the last approval of a marketing application in 
an ICH region and until there are no pending or contemplated marketing applications in an ICH 
region or at least 2 years have elapsed since the formal discontinuation of clinical development 
of the investigational product. 
Dates marking the beginning of the final record retention periods will be sent in writing from 
CRO/Sponsor.  If an Investigator withdraws from the study (eg, relocation), the records will be 
transferred to a mutually agreed upon designee (ie, another Investigator).  This transfer is subject 
to Sponsor approval and will be documented in writing and a copy sent to the Sponsor. 
Electronic Data Capture Data Archiving: 
In compliance with data retention requirements and after the capture phase of the study is 
complete; the site will receive the study and system documentation and a copy of all eSource and 
study data from EDC vendors.  The vendors shall certify the integrity of the copy (certified copy) 
and send it on commonly readable storage material (currently CD ROM).  This read-only archive 
will be retained, protected and made accessible by the site throughout the required retention 
period. 
 
21.11. 
Inspection of Records 
In the event of an inspection, the Investigator agrees to allow representatives of the Sponsor, its 
representative, the Food and Drug Administration or other regulatory authorities access to all 
study records.  The Investigator will promptly notify CRO/Sponsor of all requests to inspect by 
government agencies and will promptly forward a copy of all such inspection reports. 
 
21.12. 
Financial Disclosure 
Prior to the start of the study, Investigators will release sufficient and accurate financial 
information that permits CRO/Sponsor to demonstrate that an Investigator and all 
sub-Investigators listed on the FDA Form 1572, if appropriate, have no personal or professional 
financial incentive regarding the future approval or disapproval of the study drug such that his or 
her research might be biased by such incentive.  Investigators will provide an update of the 
above financial information at the end of the study and one year following the end of the study. 


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22. 
APPENDIX II. 
CLINICAL LABORATORY TESTS 
HEMATOLOGYa 
BLOOD CHEMISTRIESa 
1.  Total WBC Count 
1.  Electrolytes: 
2.  Differential: 
 
Bicarbonate (HCO3) 
 
Neutrophils 
 
Calcium (Ca) 
 
Lymphocytes 
 
Chloride (Cl) 
 
Monocytes 
 
Phosphorus (P) 
 
Eosinophils 
 
Potassium (K) 
 
Basophils 
 
Sodium (Na) 
3.  Hemoglobin 
 
Magnesium (Mg) 
4.  Hematocrit 
2.  Enzymes: 
5.  RBC Count 
 
Alkaline Phosphatase (ALP) 
6.  Platelet Count 
 
Aspartate aminotransferase (AST) 
QUALITATIVE URINALYSISa 
 
Alanine aminotransferase (ALT) 
Creatinine phosphokinase (CPK) 
1.  Glucose 
3.  Other: 
2.  Ketones 
 
Albumin 
3.  Protein 
 
Bilirubin (Total, Direct, Indirect) 
4.  Blood 
 
Creatinine 
5.  pH 
 
Glucose 
6.  Leukocyte esterace 
 
Protein (Total) 
7.  Urobilinogen 
 
Blood Urea Nitrogen (BUN) 
8.  Nitrites 
 
Uric Acid 
QUANTITATIVE URINALYSIS 
 
 
1.  Microscopic Examination  
 
 
DRUG SCREENINGb 
OTHER TESTS 
1.  Barbiturates 
1.  Coagulation (PT/INR, PTT) 
2.  Benzodiazepines 
2.  Serum Pregnancy (β-HcG) (female 
subjects of child bearing potential 
only) 
3.  Cannabinoids 
3.  Thyroid (free T3, free T4, and TSH) 
4.  Cocaine 
5.  Amphetamines 
4.  Bone Turnover Markers (serum 
25-OHD, PTH, osteocalcin, 
bone-specific ALP, and urinary NTx) 
6.  Opiates 
5.  Lipid Panel (cholesterol, 
HDL-cholesterol, LDL-cholesterol, 
and triglycerides)a 
Abbreviations:  CPK=creatinine phosphokinase; 25-OHD=25-hydroxyvitamin D; HDL=high-density lipoprotein; 
INR=international normalized ratio; LDL=low-density lipoprotein; PT=prothrombin time; PTH=parathyroid hormone; 
PTT=partial thromboplastin time; NTx=N-telopeptides of type I collagen cross-links; TSH=thyroid stimulating hormone; 
V=visit; WBC=while blood cells. 
a.  Fasting labs.   
b.  Performed at Visit 1 only.  Visit 1 of this study corresponds to Visit 9 of Protocols 093-045 and 093-046.  The 
following procedures are also performed at Visit 9 of Protocols 093-045 and 093-046 and therefore do not have to be 
duplicated in the present study.  The results are applicable to this study as well. 
 


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Laboratory reports will be initialed and dated on all pages by a 1572-listed investigator (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. 
Abnormal laboratory findings will be rated according to the following scale: 
1 = Deviation from reference range and not clinically significant; not related to underlying 
condition or disease; 
2 = Deviation from reference range and not clinically significant; related to any underlying 
condition or disease; or 
3 = Deviation from reference range and clinically significant (to be followed until 
normalized or new baseline; if post-screening, a corresponding AE must be recorded). 
A positive drug screen does not require a deviation code. 
 
 


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23. 
APPENDIX III.  CARDIAC SAFETY MONITORING/ECG 
I.  Requirements for Testing 
 
ECG equipment and supplies will be provided by the ECG Core Lab and should be used for all 
in-clinic protocol ECG assessments. 
 
All 12-lead ECGs will be recorded in the same manner. 
 
• The site personnel must be able to demonstrate documentation of adequate training in 
performing ECGs on the specific ECG equipment used in this protocol that is provided 
by the ECG Core Lab. 
 
• To the extent possible, the same ECG machine and personnel should be used for the 
subject’s period of participation in the study. 
 
• All ECGs will be recorded with at least one 10-second single-lead rhythm strip 
recorded from Lead II. 
 
• All ECGs will be electronically transmitted to the ECG Core Lab daily. 
 
II.  Subject Restrictions and Instructions 
 
• Prior to ECG acquisition, the subject will have rested 10 minutes in the supine 
position and will remain so when the ECG is obtained. 
 
III.  Reporting 
 
• It is the responsibility of the Investigator to perform a safety review of all ECG data 
for changes from previous assessments and/or emergent cardiac dysfunction, and to 
determine subjects’ eligibility or continuance in the study. 
 
• All ECGs waveforms and over-read (if applicable) reports will be reviewed, signed 
and dated by an Investigator listed on the FDA 1572 (MD or DO).  The same 
Investigator should review all ECG reports for a given subject whenever possible. 
 
• For all ECGs, a report will be provided by the cardiac safety vendor to the site for 
review and signature. 
 
• Waveforms and over-read (if applicable) reports will be kept with the subject’s source 
documentation and/or eCRF unless it is specified otherwise. 
 
• Original waveforms and over-read (if applicable) reports will be retained at the site. 
 
 


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IV.  Data Standardization 
 
All ECGs will be centrally over-read (except for the post-1-year EOS/ET ECG, if performed) 
and interpreted using standard procedures at the ECG Core Lab. 


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24. 
APPENDIX IV.   DEFINITIONS FOR REPORTING ADVERSE 
EVENTS 
The Investigator must assess the severity of the adverse event using the following: 
• Mild - awareness of event but easily tolerated. 
• Moderate - discomfort enough to cause some interference with normal activity. 
• Severe - inability to carry out usual activity. 
The Investigator must assess the relationship of the adverse event to the study drug using the 
following: 
• Not related – improbable temporal relationship and is plausibly related to other drugs or 
underlying disease. 
• Unlikely – occurred within a reasonable time frame after administration/discontinuation 
of study drug, but there is a likely association of an intercurrent/underlying medical 
condition or other drugs.  
• 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.   
• 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. 
Frequency will be defined using the following terms and definitions: 
• Once – an isolated episode. 
• Intermittent – occurs on two or more separate occasions. 
• Continuous – does not abate from date of onset to date of resolution. 
The action taken regarding study drug will be defined as follows: 
• Dose not changed – no change 
• Dose interrupted – study drug stopped temporarily. 
• Dose modified – study drug decreased or increased. 
• Dose withdrawn – study drug stopped permanently. 


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25. 
APPENDIX V.  STRUCTURED INTERVIEW GUIDE FOR THE 
MONTGOMERY-ASBERG DEPRESSION RATING SCALE 
(MADRS) (SIGMA)  
The rating should be based on a clinical interview moving from broadly phrased questions about 
symptoms to more detailed ones which allow a precise rating of severity.  The rater must decide 
whether the rating lies on predefined scale steps (0, 2, 4, 6) or between them (1, 3, 5). 
It is important to remember that it is only on rare occasions that a depressed patient is 
encountered who cannot be rated on the items in the scale.  If definite answers cannot be elicited 
from the patient all relevant clues as well as information from other sources should be used as a 
basis for the rating in line with customary clinical practice. 
The scale may be used for any time interval between ratings, be it weekly or otherwise, but this 
must be recorded. 
Item List 
1. 
Apparent sadness 
2. 
Reported sadness 
3. 
Inner tension 
4. 
Reduced sleep 
5. 
Reduced appetite 
6. 
Concentration difficulties 
7. 
Lassitude 
8. 
Inability to feel 
9. 
Pessimistic thoughts 
10. Suicidal thoughts 
 


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1. Apparent Sadness 
Representing despondency, gloom and despair, (more than just ordinary transient low 
spirits) reflected in speech, facial expression, and posture.  Rated by depth and inability 
to brighten up. 
 
0 No sadness. 
1 
2 Looks dispirited but does brighten up without difficulty. 
3 
4 Appears sad and unhappy most of the time. 
5 
6 Looks miserable all the time.  Extremely despondent. 
 
2. Reported sadness 
Representing reports of depressed mood, regardless of whether it is reflected in 
appearance or not.  Includes low spirits, despondency or the feeling of being beyond help 
and without hope.  Rate according to intensity, duration and the extent to which the mood 
is reported to be influenced by events. 
0 
Occasional sadness in keeping with the circumstances. 
1 
2 
Sad or low but brightens up without difficulty. 
3 
4 
Pervasive feelings of sadness or gloominess.  The mood is still influenced by 
external circumstances. 
5 
6 
Continuous or unvarying sadness, misery or despondency. 
 


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3. Inner tension 
Representing feeling of ill-defined discomfort, edginess, inner turmoil, mental tension 
mounting to either panic, dread or anguish.  Rate according to intensity, frequency, 
duration and the extent of reassurance called for. 
 
0 Placid.  Only fleeting inner tension. 
1 
2 Occasional feelings of edginess and ill-defined discomfort. 
3 
4 Continuous feelings of inner tension or intermittent panic which the patient can only 
master with some difficulty. 
5 
6 Unrelenting dread or anguish. Overwhelming panic. 
 
4. Reduced sleep 
Representing the experience of reduced duration or depth of sleep compared with the 
subject’s own normal pattern when well. 
 
0 Sleeps as usual. 
1 
2 
Slight difficulty dropping off to sleep or slightly reduced, light or fitful sleep. 
3 
4 Sleep reduced or broken by at least two hours. 
5 
6 Less than two or three hours sleep. 
 


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5. Reduced appetite 
Representing the feeling of a loss of appetite compared with when well.  Rate by loss of 
desire for food or the need to force oneself to eat. 
0 Normal or increased appetite. 
1 
2 Slightly reduced appetite. 
3 
4 No appetite.  Food is tasteless. 
5 
6 Needs persuasion to eat at all. 
 
 
6. Concentration difficulties 
Representing difficulties in collecting one’s thoughts mounting to incapacitating lack of 
concentration.  Rate according to intensity, frequency, and degree of incapacity 
produced. 
 
0 No difficulties in concentrating. 
1 
2 Occasional difficulties in collecting one’s thoughts. 
3 
4 
Difficulties in concentration and sustaining thought which reduces ability to read or 
hold a conversation. 
5 
6 Unable to read or converse without great difficulty. 
 
 


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7. Lassitude 
Representing a difficulty getting started or slowness initiating and performing 
everyday activities. 
 
0 Hardly any difficulty in getting started.  No sluggishness. 
1 
2 Difficulties in starting activities. 
3 
4 
Difficulties in starting simple routine activities which are carried out with effort. 
5 
6 Complete lassitude.  Unable to do anything without help. 
 
8. Inability to feel 
Representing the subjective experience of reduced interest in the surroundings, or 
activities that normally give pleasure.  The ability to react with adequate emotion to 
circumstances or people is reduced. 
0 Normal interest in the surroundings and in other people. 
1 
2 Reduced ability to enjoy usual interests. 
3 
4 
Loss of interest in the surroundings.  Loss of feelings for friends and acquaintances. 
5 
6 
The experience of being emotionally paralyzed, inability to feel anger, grief or 
pleasure and a complete or even painful failure to feel for close relatives and friends. 
 
 


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9. Pessimistic thoughts 
Representing thoughts of guilt, inferiority, self-reproach, sinfulness, remorse 
and ruin. 
0 No pessimistic thoughts. 
1 
2 Fluctuating ideas of failure, self-reproach or self-depreciation. 
3 
4 
Persistent self-accusations, or definite but still rational ideas of guilt or sin. 
Increasingly pessimistic about the future. 
5 
6 
Delusions of ruin, remorse or unredeemable sin.  Self-accusations which are absurd 
and unshakable. 
 
10. Suicidal thoughts 
Representing the feeling that life is not worth living, that a natural death would be 
welcome, suicidal thoughts and preparations for suicide. 
Suicidal attempts should not in themselves influence the rating. 
 
0 Enjoys life or takes it as it comes. 
1 
2 Weary of life.  Only fleeting suicidal thoughts. 
3 
4 
Probably better off dead.  Suicidal thoughts are common and suicide is considered as 
a possible solution, but without specific plans or intention. 
5 
6 Explicit plans for suicide when there is an opportunity.  Active preparations for 
suicide. 
 
Reproduced from:  A new depression scale designed to be sensitive to change. S.A. Montgomery & M. Åsberg, 
British Journal of Psychiatry (1979), 134, 382-389. © 1979 The Royal College of Psychiatrists. 


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26. 
APPENDIX VI.  31-ITEM QUALITY OF LIFE IN EPILEPSY 
SCALE (QOLIE-31)  


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27. 
APPENDIX VII.  COLUMBIA-SUICIDE SEVERITY RATING 
SCALE (C-SSRS) 
COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Baseline 
 
  
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.  
 
Disclaimer: 
This scale is intended for use by trained clinicians. The questions contained in the 
Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the 
determination of the presence of suicidality depends on clinical judgment. 
 
Definitions of behavioral suicidal events in this scale are based on those used in 
The Columbia Suicide History Form, developed by John Mann, MD and Maria 
Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, 
NY, 10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk factors for suicidal 
behavior: utility and limitations of research instruments. In M.B. First [Ed.] 
Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
 For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric 
Institute, 1051 Riverside Drive, New York, New York, 10032; inquiries contact 
posnerk@childpsych.columbia.edu  


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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 
is “yes,” ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of 
Ideation” section below. 
 
Lifetime:  
Time 
He/She Felt 
Most 
Suicidal 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g. “I’ve thought about killing myself”) without thoughts of 
ways to kill oneself/associated methods, intent, or plan.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific 
plan with time, place or method details worked out (e.g.  thought of method to kill self but not a specific plan).  Includes person who would 
say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do it…..and I would 
never go through with it”.  
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
 Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the 
thoughts but I definitely will not do anything about them”. 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
 Yes      No 
 □    □ 


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INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from above, with 1 being the 
least severe and 5 being the most severe ). Ask about time he/she was feeling the most suicidal.  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time 
____ 
Controllability 
Could /can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g. family, religion, pain of death) - that stopped you from wanting to die 
or acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply; wish to die only 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or 
stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or 
was it to get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others.       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others.                     living with the pain or how you were feeling). 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain.                                                                          living with the pain or  how you were feeling). 
 
 
____ 


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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
 
Lifetime  
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual 
suicide attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while 
gun is in mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For 
example, a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g. gunshot to head, jumping from 
window of a high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be 
inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, 
get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
 
Yes    No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt 
would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an 
interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from 
pulling trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and 
taken down from ledge. Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you 
before you actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself before you 
actually did anything? 
If yes, describe: 
 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g. buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g. giving things away, writing a 
suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
 


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Answer for Actual Attempts Only 
Most 
Recent 
Attempt 
Most 
Lethal     
Attempt 
Initial/First 
Attempt 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g. surface scratches). 
1.  Minor physical damage (e.g. lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g. conscious but sleepy, somewhat responsive; 
second-degree burns; bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g. 
comatose with reflexes intact; third-degree burns less than 20% of body; extensive blood loss but can 
recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g. comatose without 
reflexes; third-degree burns over 20% of body; extensive blood loss with unstable vital signs; major 
damage to a vital area). 
5.  Death 
 
 
Date 
 
 
 
 
Enter 
# 
 
 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual 
medical damage, had potential for very serious lethality: put gun in mouth and pulled the trigger but gun 
fails to fire so no medical damage; laying on train tracks with oncoming train but pulled away before run 
over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
Date 
 
 
 
 
Enter 
# 
 
 
 
 


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COLUMBIA-SUICIDE SEVERITY 
RATING SCALE 
(C-SSRS) 
Since Last Visit 
 
  
Posner, K.; Brent, D.; Lucas, C.; Gould, M.; Stanley, B.; Brown, G.; Fisher, P.; 
Zelazny, J.; Burke, A.; Oquendo, M.; Mann, J.  
 
Disclaimer: 
This scale is intended for use by trained clinicians. The questions contained in the 
Columbia-Suicide Severity Rating Scale are suggested probes. Ultimately, the 
determination of the presence of suicidality depends on clinical judgment. 
 
Definitions of behavioral suicidal events in this scale are based on those used in 
The Columbia Suicide History Form, developed by John Mann, MD and Maria 
Oquendo, MD, Conte Center for the Neuroscience of Mental Disorders 
(CCNMD), New York State Psychiatric Institute, 1051 Riverside Drive, New York, 
NY, 10032. (Oquendo M. A., Halberstam B. & Mann J. J., Risk factors for suicidal 
behavior: utility and limitations of research instruments. In M.B. First [Ed.] 
Standardized Evaluation in Clinical Practice, pp. 103 -130, 2003.) 
 
 For reprints of the C-SSRS contact Kelly Posner, Ph.D., New York State Psychiatric 
Institute, 1051 Riverside Drive, New York, New York, 10032; inquiries contact 
posnerk@childpsych.columbia.edu  
 


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SUICIDAL IDEATION 
Ask questions 1 and 2.  If both are negative, proceed to “Suicidal Behavior” section. If the answer to question 2 
is “yes,” ask questions 3, 4 and 5.  If the answer to question 1 and/or 2 is “yes”, complete “Intensity of 
Ideation” section below. 
 
Since 
Last 
Visit 
1.  Wish to be Dead  
Subject endorses thoughts about a wish to be dead or not alive anymore, or wish to fall asleep and not wake up.  
Have you wished you were dead or wished you could go to sleep and not wake up?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
2.  Non-Specific Active Suicidal Thoughts 
General, non-specific thoughts of wanting to end one’s life/commit suicide (e.g. “I’ve thought about killing myself”) without thoughts of 
ways to kill oneself/associated methods, intent, or plan during the assessment period.  
Have you actually had any thoughts of killing yourself? 
 
If yes, describe: 
 
 Yes      No 
 □    □ 
3.  Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act 
Subject endorses thoughts of suicide and has thought of at least one method during the assessment period. This is different than a specific 
plan with time, place or method details worked out (e.g.  thought of method to kill self but not a specific plan).  Includes person who would 
say, “I thought about taking an overdose but I never made a specific plan as to when, where or how I would actually do it…..and I would 
never go through with it”.  
Have you been thinking about how you might do this? 
 
If yes, describe: 
 
 
 Yes      No 
 □    □ 
4.  Active Suicidal Ideation with Some Intent to Act, without Specific Plan 
Active suicidal thoughts of killing oneself and subject reports having some intent to act on such thoughts, as opposed to “I have the 
thoughts but I definitely will not do anything about them”. 
Have you had these thoughts and had some intention of acting on them?  
 
If yes, describe: 
 
 
Yes       No 
 □    □ 
5.  Active Suicidal Ideation with Specific Plan and Intent 
Thoughts of killing oneself with details of plan fully or partially worked out and subject has some intent to carry it out. 
Have you started to work out or worked out the details of how to kill yourself? Do you intend to carry out this plan? 
   
If yes, describe: 
 
 
 Yes      No 
 □    □ 


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INTENSITY OF IDEATION 
The following features should be rated with respect to the most severe type of ideation (i.e.,1-5 from above, with 1 being the 
least severe and 5 being the most severe ).  
                                             
Most Severe Ideation:             _____                      _________________________________________________ 
                                               
                                                                                                           Type # (1-5)                                         Description of  Ideation 
Most 
Severe 
Frequency 
How many times have you had these thoughts?  
(1) Less than once a week    (2) Once a week   (3)  2-5 times in week    (4) Daily or almost daily    (5) Many times each day 
 
____ 
Duration 
When you have the thoughts, how long do they last? 
(1) Fleeting - few seconds or minutes                                                 (4) 4-8 hours/most of day 
(2) Less than 1 hour/some of the time                                                 (5) More than 8 hours/persistent or continuous 
(3) 1-4 hours/a lot of time                                                                    
____ 
Controllability 
Could /can you stop thinking about killing yourself or wanting to die if you want to? 
(1) Easily able to control thoughts                                                      (4) Can control thoughts with a lot of difficulty 
(2) Can control thoughts with little difficulty                                     (5) Unable to control thoughts 
(3) Can control thoughts with some difficulty                                    (0) Does not attempt to control thoughts 
____ 
Deterrents 
Are there things - anyone or anything (e.g. family, religion, pain of death) - that stopped you from wanting to die 
or acting on thoughts of committing suicide? 
(1) Deterrents definitely stopped you from attempting suicide            (4) Deterrents most likely did not stop you  
(2) Deterrents probably stopped you                                                    (5) Deterrents definitely did not stop you  
(3) Uncertain that deterrents stopped you                                             (0) Does not apply; wish to die only 
____ 
Reasons for Ideation 
What sort of reasons did you have for thinking about wanting to die or killing yourself?  Was it to end the pain or 
stop the way you were feeling (in other words you couldn’t go on living with this pain or how you were feeling) or 
was it to get attention, revenge or a reaction from others? Or both? 
(1) Completely to get attention, revenge or a reaction from others.       (4) Mostly to end or stop the pain (you couldn’t go on 
(2) Mostly to get attention, revenge or a reaction from others.                     living with the pain or how you were feeling). 
(3) Equally to get attention, revenge or a reaction from others               (5) Completely to end or stop the pain (you couldn’t go on  
       and to end/stop the pain.                                                                         living with the pain or  how you were feeling). 
 
____ 


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SUICIDAL BEHAVIOR 
(Check all that apply, so long as these are separate events; must ask about all types) 
Since 
Last 
Visit 
Actual Attempt:  
A potentially self-injurious act committed with at least some wish to die, as a result of act. Behavior was in part thought of as method to kill 
oneself. Intent does not have to be 100%.  If there is any intent/desire to die associated with the act, then it can be considered an actual 
suicide attempt. There does not have to be any injury or harm, just the potential for injury or harm. If person pulls trigger while 
gun is in mouth but gun is broken so no injury results, this is considered an attempt.   
Inferring Intent: Even if an individual denies intent/wish to die, it may be inferred clinically from the behavior or circumstances. For 
example, a highly lethal act that is clearly not an accident so no other intent but suicide can be inferred (e.g. gunshot to head, jumping from 
window of a high floor/story). Also, if someone denies intent to die, but they thought that what they did could be lethal, intent may be 
inferred.  
Have you made a suicide attempt? 
Have you done anything to harm yourself? 
 
Have you done anything dangerous where you could have died? 
What did you do? 
Did you______ as a way to end your life?  
Did you want to die (even a little) when you_____?  
Were you trying to end your life when you _____? 
Or did you think it was possible you could have died from_____? 
Or did you do it purely for other reasons / without ANY intention of killing yourself (like to relieve stress, feel better, 
get sympathy, or get something else to happen)?  (Self-Injurious Behavior without suicidal intent) 
If yes, describe: 
 
 
Has subject engaged in Non-Suicidal Self-Injurious Behavior? 
 
Yes      No 
□   □ 
 
 
 
 
 
 
 
Total # of 
Attempts 
 
______ 
 
 
 
 
 
 
 
Yes     No 
□   □ 
Interrupted Attempt:   
When the person is interrupted (by an outside circumstance) from starting the potentially self-injurious act (if not for that, actual attempt 
would have occurred). 
Overdose: Person has pills in hand but is stopped from ingesting.  Once they ingest any pills, this becomes an attempt rather than an 
interrupted attempt. Shooting: Person has gun pointed toward self, gun is taken away by someone else, or is somehow prevented from 
pulling trigger. Once they pull the trigger, even if the gun fails to fire, it is an attempt. Jumping: Person is poised to jump, is grabbed and 
taken down from ledge. Hanging: Person has noose around neck but has not yet started to hang - is stopped from doing so. 
Has there been a time when you started to do something to end your life but someone or something stopped you 
before you actually did anything? 
If yes, describe: 
 
Yes      No 
□   □ 
 
 
Total # of 
interrupted 
 
______ 
 
Aborted Attempt:   
When person begins to take steps toward making a suicide attempt, but stops themselves before they actually have engaged in any self-
destructive behavior. Examples are similar to interrupted attempts, except that the individual stops him/herself, instead of being stopped by 
something else. 
Has there been a time when you started to do something to try to end your life but you stopped yourself 
before you actually did anything? 
If yes, describe: 
 
 
Yes      No 
□   □ 
 
Total # of 
aborted 
 
______ 
Preparatory Acts or Behavior: 
Acts or preparation towards imminently making a suicide attempt. This can include anything beyond a verbalization or thought, such as 
assembling a specific method (e.g. buying pills, purchasing a gun) or preparing for one’s death by suicide (e.g. giving things away, writing a 
suicide note).  
Have you taken any steps towards making a suicide attempt or preparing to kill yourself (such as collecting pills, 
getting a gun, giving valuables away or writing a suicide note)? 
If yes, describe: 
 
 
Yes      No 
□   □ 
Suicidal Behavior: 
Suicidal behavior was present during the assessment period? 
Yes      No 
□   □ 
Completed Suicide: 
   Yes    No 
□   □ 
 


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Page 91 of 100 
 
Answer for Actual Attempts Only 
Most 
Lethal 
Attempt 
Actual Lethality/Medical Damage:   
0.  No physical damage or very minor physical damage (e.g. surface scratches). 
1.  Minor physical damage (e.g. lethargic speech; first-degree burns; mild bleeding; sprains). 
2.  Moderate physical damage; medical attention needed (e.g. conscious but sleepy, somewhat responsive; second-degree burns; 
bleeding of major vessel). 
3.  Moderately severe physical damage; medical hospitalization and likely intensive care required (e.g. comatose with reflexes 
intact; third-degree burns less than 20% of body; extensive blood loss but can recover; major fractures). 
4.  Severe physical damage; medical hospitalization with intensive care required (e.g. comatose without reflexes; third-degree 
burns over 20% of body; extensive blood loss with unstable vital signs; major damage to a vital area). 
5.  Death 
 
 
Date 
 
 
 
Enter 
# 
 
Potential Lethality: Only Answer if Actual Lethality=0 
Likely lethality of actual attempt if no medical damage (the following examples, while having no actual medical damage, had 
potential for very serious lethality: put gun in mouth and pulled the trigger but gun fails to fire so no medical damage; laying on 
train tracks with oncoming train but pulled away before run over). 
 
0 = Behavior not likely to result in injury 
1 = Behavior likely to result in injury but not likely to cause death 
2 = Behavior likely to result in death despite available medical care  
 
 
Date 
 
 
Enter 
# 
 
 
 
 


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Confidential and Proprietary 
 
Page 92 of 100 
 
28. 
APPENDIX VIII.  
MEDICAL EVENT CALENDAR 
The Medical Event Calendar (MEC) is used to track a subject’s health status while away from 
clinic in an efficient and possibly more reliable manner than in-clinic questioning that relies 
solely on subject recollection.  They will be provided by Sunovion Pharmaceuticals Inc. for each 
study subject and are to be used throughout the study.  While at home, subjects will daily record: 
• Any new medications taken not already reported to clinic staff. 
• Any emergent symptoms that occur, regardless of their relationship or the period of study 
participation. 
Study Staff will review, sign, and date the MEC at the beginning of each clinic visit.  
Emergent AEs should be recorded onto the eCRF using medically correct terminology and not 
necessarily using the verbatim subject report from the MEC.  The relationship between an MEC 
entry and what is recorded in the eCRF should be noted in the source documentation if the 
subject verbatim term is not used in the eCRF.   
Symptoms that are consistent in nature, frequency and severity with conditions noted in the 
pre-study Medical History do not need to be recorded on the MEC and will not be captured on 
the AE eCRF page.  However, if a symptom is recorded on the MEC that is greater in frequency 
or intensity from that reported pre-study, this will be included in the eCRF.  When possible, 
diagnoses should be recorded on the AE eCRF page and not a list of the individual symptoms 
comprising the diagnosis.  For example, MEC symptoms recorded as “chills”, “headache”, 
“fever” which occur in conjunction with each other should be recorded in the eCRF as 
“influenza” after discussion of the symptoms with the subject and based on the appropriate 
medical interpretation. 
A sample is attached on the following page. 
 


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Eslicarbazepine Acetate Monotherapy Study  
Final Protocol No. 093-050, Version 6.0                                                       
07 Jun 2013 
Confidential and Proprietary 
 
Page 94 of 100 
 
29. 
APPENDIX IX.  COMPUTERIZED SYSTEMS USED FOR 
SOURCE DATA  
The following table identifies each step at which a computerized system will be used to create, 
modify, maintain, archive, retrieve, or transmit source data. 
 
Protocol Stepa 
System Type or Description 
A 
EDC (Inform) 
B 
LIMS 
C 
Core Lab Overreadb 
D 
LIMS/Excel Spreadsheet 
Statistical Analysis 
SAS® 
Abbreviations:  EDC=Electronic Data Capture; LIMS=Laboratory Information 
Management System. 
a. A letter (eg, “A”) identified in the Protocol Step column refers back to the 
Schedule of Assessment table. 
b. Not applicable for post-1-year EOS/ET ECG assessment, if performed. 
 
 
 


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30. 
APPENDIX X. SEIZURE DIARY 
 
 


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Eslicarbazepine Acetate Monotherapy Study  
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Page 97 of 100 
 
31. 
APPENDIX XI. DIASTAT® (DIAZEPAM RECTAL GEL) DOSING 
CHART 
 
 


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32. 
APPENDIX XII. DESCRIPTION OF TREATMENT OPTIONS IN 
COUNTRIES WHERE LORAZEPAM AS RESCUE 
MEDICATION IS NOT AVAILABLE 
Rescue treatment for seizures requiring administration of benzodiazepines will use the treatment 
options as listed below in order of preference.  The first listed treatment option should be 
selected that is approved by applicable regulatory bodies and in accordance with the 
standard-of-care in the country concerned.  
 
Rescue Medication 
Dose 
Route 
Comments 
Lorazepam tablets 
2 mg 
oral 
Prescription of 1 x 2 mg or 
2 x 1 mg tablets as 
available 
Diazepam tablets 
5 mg 
oral 
-- 
Diazepam drops 
5 mg 
oral 
-- 
 


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33. 
APPENDIX XIII.  DESCRIPTION OF TREATMENT OPTIONS IN 
COUNTRIES WHERE DIASTAT® (DIAZEPAM RECTAL GEL) 
AS EMERGENCY MEDICATION IS NOT AVAILABLE 
Emergency treatment for breakthrough seizures (including repeated seizures and status 
epilepticus) requiring administration of benzodiazepines will use the treatments listed below in 
order of preference.  The first listed treatment should be selected which is approved by 
applicable regulatory bodies in the patient's locale and/or based on the patient’s condition.  
 
Emergency Medication 
Dose 
Route 
Comments 
Diazepam rectal gel 
0.2 mg/kg rounded to 
2.5 mg increment 
rectal 
AcuDial® applicator allows 
person applying drug to select 
the prescribed dose. 
Diazepam solution  
-- 
rectal 
Dose to be determined by 
investigator. 
Diazepam tablets 
5-10 mg 
oral 
-- 
Diazepam solutions  
5-10 mg 
intra muscular 
Requires training of person 
administering drug.  The 
Diazepam AutoInjector® 
delivers 10 mg in a single dose. 
Diazepam drops 
5-10 mg 
oral 
-- 
 


Eslicarbazepine Acetate Monotherapy Long-Term Study  
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Confidential and Proprietary 
 
Page 100 of 100 
34. 
APPENDIX XIV.  PATIENT GLOBAL IMPRESSION (PGI) 
SCALE 
 
Global Improvement  
Please rate your overall condition compared to 
before you started the clinical study. 
 
Very much improved                               
Improved                                                   
No change                                                 
Worse                                                       
Very much worse 
 

SAP_000.pdf: 
 
Statistical Analysis Plan  
Sunovion Inc. 
093-050 
Page 1 of 34 
 
Author: 
Hanaa Girgis 
Version: Final  
Version Date:  19May2017 
Copyright © 2010 Quintiles Transnational Corp.  All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp.  Unauthorized use, disclosure 
or reproduction is strictly prohibited. 
 
 
 
STATISTICAL ANALYSIS PLAN 
 
Long-Term Eslicarbazepine Acetate Extension Study 
 
Protocol No.  093-050 
 
 
 
 
 
Prepared by QuintilesIMS Inc. 
4820 Emperor Boulevard 
Durham, NC 27703 
USA 
 
Prepared for 
Sunovion Pharmaceuticals Inc. 
84 Waterford Drive 
Marlborough, MA 01752 
USA 






 
Statistical Analysis Plan  
Sunovion Inc. 
093-050 
Page 4 of 34 
 
Author: 
Hanaa Girgis 
Version: Final  
Version Date:  19May2017 
Copyright © 2010 Quintiles Transnational Corp.  All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp.  Unauthorized use, disclosure 
or reproduction is strictly prohibited. 
Table of contents 
Statistical Analysis Plan Signature Page - Authors .............................................................. 2 
Statistical Analysis Plan Signature Page - Approval ............................................................ 3 
Table of contents ...................................................................................................................... 4 
List of abbreviations and definition of terms ........................................................................ 6 
1.
Introduction ................................................................................................................... 7 
2.
Study objectives ............................................................................................................. 7 
2.1. Primary objective .................................................................................................................. 7 
2.2. Secondary objectives ............................................................................................................ 7 
3.
Study design ................................................................................................................... 7 
3.1. General Description .............................................................................................................. 7 
3.2. Study Schematic ................................................................................................................... 9 
3.3. Determination of Sample Size .............................................................................................. 9 
4.
Changes in the Conduct of the Study or Planned Analysis ....................................... 9 
4.1. Changes in the Conduct of the Study ................................................................................... 9 
4.2. Changes from Analyses Planned in the Protocol .................................................................. 9 
5.
Efficacy and Safety Variables ..................................................................................... 10 
5.1. Schedule of Evaluations ..................................................................................................... 10 
5.2. 
Efficacy Assessment and Endpoints ............................................................................. 12 
5.2.1.
Assessments .................................................................................................................... 12 
5.2.2.
1-Year Open-Label Period Efficacy Endpoints .............................................................. 12 
5.2.3.
Post-1-Year Open-Label Period Endpoints .................................................................... 14 
5.2.4.
Entire Open-Label Period Endpoints..............................................................................16
5.3. 
Safety Assessments and Endpoints............................................................................... 19 
5.3.1.
Safety Assessments ........................................................................................................ 19 
5.3.2.
Safety Endpoints ............................................................................................................. 20 
6.
Statistical Methods ...................................................................................................... 24 
6.1 
General Methodology ................................................................................................... 24 
6.2 
Handling of Dropouts or Missing Data ........................................................................ 24 
6.3 
Interim Analyses and Data Monitoring ........................................................................ 25 
6.4 
Multiple Comparisons/Multiplicity .............................................................................. 25 
6.5 
Examination of Subgroups ........................................................................................... 25 
7.
Statistical Analysis ....................................................................................................... 26 
7.1 Analysis Populations ........................................................................................................... 26 
7.2 Disposition of Subjects ........................................................................................................ 26 
7.3 Protocol Deviations ............................................................................................................. 27 
7.4 Demographic and Other Baseline Characteristics ............................................................... 27 
7.5 Extent of Exposure and Compliance ................................................................................... 27 
7.6 Efficacy Analyses ................................................................................................................... 29 
7.7 Safety Analyses ................................................................................................................... 31 


 
Statistical Analysis Plan  
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Author: 
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or reproduction is strictly prohibited. 
7.7.1 
Adverse Events ............................................................................................................... 31 
7.7.2 Clinical Laboratory Evaluation ............................................................................................ 32 
7.7.3 ECG Evaluations .................................................................................................................. 32 
7.7.4 Vital Signs............................................................................................................................ 33 
7.7.5 Orthostatic Effects ............................................................................................................... 33 
7.7.6 Physical and Neurological Examinations ............................................................................. 33 
7.7.7 Concomitant Medication ...................................................................................................... 34 
7.7.8 
Columbia-Suicide Severity Rating Scale (C-SSRS) ....................................................... 34 
8.
References .................................................................................................................... 34 


 
Statistical Analysis Plan  
Sunovion Inc. 
093-050 
Page 6 of 34 
 
Author: 
Hanaa Girgis 
Version: Final  
Version Date:  19May2017 
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The contents of this document are confidential and proprietary to Quintiles Transnational Corp.  Unauthorized use, disclosure 
or reproduction is strictly prohibited. 
List of abbreviations and definition of terms 
25-OHD 
Serum 25-hydroxyvitamin D 
AE 
Adverse Event 
AEDs 
Anti-Epileptic Drugs 
ALT 
Alanine Aminotransferase
aPTT 
Activated Partial Thromboplastin Time 
AST 
Aspartate Aminotransferase 
BMI 
Body Mass Index 
BP 
Blood Pressure 
bpm 
Beats per Minute 
BUN 
Blood Urea Nitrogen 
eCRF 
Electronic Case Report Form 
C-SSRS 
Columbia-Suicide Severity Rating Scale 
ECG 
Electrocardiogram 
EENT
Eyes, Ears, Nose, and Throat
ESL 
Eslicarbazepine acetate 
HDL 
High Density Lipoprotein 
INR 
International Normalized Ratio 
IPD 
Important Protocol Deviation 
ITT 
Intent-to-Treat 
LDL 
Low Density Lipoprotein 
MADRS 
Montgomery-Asberg Depression Rating Scale 
MEC 
Medical Events Calendar 
MedDRA 
Medical Dictionary for Regulatory Affairs 
N/A 
Not Applicable 
NTx 
N-telopeptides of type I collagen cross-links 
PCS 
Potentially Clinically Significant 
PGI 
Patient Global Impression 
PT 
Prothrombin Time 
PTH 
Parathyroid Hormone 
PTT 
Partial Thromboplastin Time 
QD 
Once Daily 
QOLIE 
Quality of Life in Epilepsy 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SSF 
Standardized Seizure Frequency 
TEAE 
Treatment-Emergent Adverse Event 
ULN 
Upper Limit of Normal 
WHO 
World Health Organization 
 


 
Statistical Analysis Plan  
Sunovion Inc. 
093-050 
Page 7 of 34 
 
Author: 
Hanaa Girgis 
Version: Final  
Version Date:  19May2017 
Copyright © 2010 Quintiles Transnational Corp.  All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp.  Unauthorized use, disclosure 
or reproduction is strictly prohibited. 
1. Introduction 
This document describes the rules and conventions to be used in the presentation and 
analysis of efficacy and safety data for protocol 093-050.  It describes, in detail, the 
data and endpoints to be summarized and analyzed, including specifics of the 
statistical analyses to be performed.   
This Statistical Analysis and Reporting Plan (SAP) is based on protocol version 6.0, 
dated 7June2013. 
2. Study objectives 
The objective of this study is to confirm the long-term safety and maintenance of 
effect of eslicarbazepine acetate (flexible dose range of 800 mg to 2400 mg) in 
subjects with partial onset seizures, with or without secondary generalization, not well 
controlled by current AEDs.   
2.1. Primary objective 
To evaluate the 1-Year Open-Label Period and Post-1-Year Open-Label Period safety 
and tolerability of eslicarbazepine acetate flexible dosing within the range of 800 mg 
to 2400 mg in subjects with partial epilepsy who have participated in an 18-week 
double-blind eslicarbazepine acetate monotherapy study (Protocols 093-045 or 093-
046).   
2.2. Secondary objectives 
• To evaluate the maintenance of the therapeutic effects of eslicarbazepine acetate 
over a 1-Year Open-Label Period and Post-1-Year Open-Label Period.   
• To evaluate the health-related quality-of-life, suicidality, and depressive 
symptoms over a 1-Year Open-Label Period and Post-1-Year Open-Label Period.   
3. Study design 
3.1. General Description 
This study is a long-term, multicenter, open-label, safety extension study in male and 
female subjects (aged 16 to 70 years, inclusive) with partial onset seizures who have 
just completed, discontinued, or exited the 18-week treatment phase of Protocols 093-
045 or 093-046.  The initial study duration is 1-Year Open-Label Period with the 
option of continuing study drug treatment Post-1-Year Open-Label Period until a 
subject discontinues study, the study drug becomes clinically available in the subject’s 
locale, or the sponsor terminates the study drug clinical development program.   
This study will evaluate the safety and maintenance of effect of long-term 
eslicarbazepine acetate treatment at flexible doses in the range of 800 mg to 2400 mg 
once-a-day (QD) over a 1-Year Open-Label Period and a Post-1-Year Open-Label 
Period.   


 
Statistical Analysis Plan  
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093-050 
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Author: 
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Version Date:  19May2017 
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or reproduction is strictly prohibited. 
Subjects who enter the present study will receive a starting dose of 1600 mg QD of 
eslicarbazepine acetate, orally for 1 week at the start of the 1-Year Open-Label Period.  
The starting dose for subjects who had a dose reduction during participation in studies 
093-045 or 093-046 will be 1200 mg and not 1600 mg.  At the end of this 1-week 
period, subjects will be allowed to continue at this dose or at the discretion of the 
Investigator, increase, or decrease dose as necessary for efficacy or tolerability 
reasons.  There is no limit on the number of dose increments or reductions during the 
study, however, all dose increases or reductions should occur in steps of 400 mg and a 
minimum of 1 week must pass between one dose change and the next.  Dose 
reductions of more than 400 mg are allowed at the discretion of the Investigator for a 
documented safety reason.  The maximum allowed dose of eslicarbazepine acetate is 
2400 mg QD and the minimum allowed dose is 800 mg QD in this study.  Subjects 
who continue into the Post-1-Year Open-Label Period part of the study will continue 
to receive the same dose of study drug that they received at Visit 7 (end of 1-Year 
Open-Label Period of treatment).  The same dosing rules as in the 1-Year Open-Label 
Period part of the study are applicable in the Post-1-Year Open-Label Period part.  
Subjects with a clinically significant increase in seizure frequency, duration, or 
severity, who have not responded to or did not tolerate an increase in dose of study 
drug, may be started on an additional antiepileptic drug (AED) during both the 1-Year 
Open-Label Period and Post-1-Year Open-Label Period parts of the study.  A 
maximum of two additional AEDs to control seizures will be allowed, however 
oxcarbazepine will not be allowed.  If, after the addition of the second additional 
AED, the subject experiences an adverse event, the dose of eslicarbazepine acetate 
should be reduced before changing the dose of the concomitant AED.  In addition, for 
subjects with a vagal nerve stimulator (VNS), the device setting may be changed as 
needed.   
Subjects who require doses outside of the 800 mg QD to 2400 mg QD range or more 
than 2 additional AEDs during the 1-Year Open-Label Period or Post-1-Year Open-
Label Period parts of the study will be discontinued from study participation.   
Physicians may prescribe lorazepam for rescue use.  Diazepam (rectal gel) as an 
emergency medication will be provided by the sponsor (via prescription from local 
physician).  In countries where lorazepam and/or diazepam rectal gel are not available, 
alternate treatments are allowed per Appendices XII and XIII in the protocol.   
 


 
Statistical Analysis Plan  
Sunovion Inc. 
093-050 
Page 9 of 34 
 
Author: 
Hanaa Girgis 
Version: Final  
Version Date:  19May2017 
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The contents of this document are confidential and proprietary to Quintiles Transnational Corp.  Unauthorized use, disclosure 
or reproduction is strictly prohibited. 
3.2. Study Schematic 
 
 
3.3. Determination of Sample Size 
Subjects will continue on to this study from Protocols 093-045 or 093-046 as of their 
own choosing.  Therefore, the sample size is outside of statistical considerations.   
4. Changes in the Conduct of the Study or Planned Analysis 
4.1. Changes in the Conduct of the Study 
Six amendments have been incorporated into protocol 093-050 since final protocol. 
4.2. Changes from Analyses Planned in the Protocol  
 The following change was made to the analysis planned in the protocol. This change 
was made prior to finalization of the SAP and prior to database lock. 
The protocol in Section 7.2.3 indicates that the fraction of subjects who completed 
treatment at each visit post-1-year will be summarized. The change to this endpoint is 
that the fraction of subjects who completed treatment only for the entire post-1-year 
period will be summarized. 
 


 
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5. Efficacy and Safety Variables 
5.1. Schedule of Evaluations 
Procedures 
Visit 1/ 
SCNa 
Visit 2 
Visit 
3 
Visit 
4 
Visits 5 
and 6 
Visit 7 
Post-1-year 
Visit 8 onwards  
EOS/ET 
Computer 
Systemsc 
Day 0 
Week 
1 
Mont
h 1 
Mont
h 3 
Months 6 
and 9 
Month 12 
Month 15 
onwardsb 
Informed Consent 
X 
 
 
 
 
 
 
 
 
Inclusion/Exclusion Criteria Review 
X 
 
 
 
 
 
 
 
A 
Physical Examination 
•d 
 
 
 
 
 
 
X 
A 
Neurological Examination 
• 
 
 
 
 
 
X
A
Vital Sign Measurements  
• 
X 
X 
X 
X 
X 
X 
X 
A 
Height 
• 
 
 
 
 
 
 
X 
A 
Weighte 
• 
X 
X 
X 
X 
X 
X 
X 
A 
Clinical Laboratory Evaluation (Serum Chemistry, 
Hematology, and Urinalysis)f 
• 
 
X 
X 
X 
X 
 
Xg,h 
B 
Coagulation Testing (PT/INR, PTT) 
• 
 
X 
X 
X 
X 
 
Xg 
B 
Thyroid Panel (T3, T4, and TSH) 
• 
 
X 
X 
X 
X 
 
Xg 
B 
Lipid Panel (total cholesterol, HDL-cholesterol, 
LDL-cholesterol, and triglycerides)f 
• 
 
X 
X 
X 
X 
 
Xg,h 
B 
Bone Turnover Markersi 
• 
 
 
 
Xh 
X 
 
Xg 
B 
Serum Pregnancy Testk 
• 
 
X 
X 
X 
X 
 
Xg 
B 
Urine Pregnancy Testk 
 
 
 
 
 
 
X 
X 
 
Urine Drug Screen (Central Lab) 
• 
 
 
 
 
 
 
 
B 
12-Lead ECG 
• 
 
X 
X 
X 
X 
 
Xh 
C 
MADRS 
• 
 
 
 
Xj
X 
Xl 
X 
A 
QOLIE-31m 
•
 
 
 
Xj
X 
Xil 
X 
A 
PGI Scale 
 
 
 
 
 
 
X 
Xn 
 
C-SSRSo 
• 
X 
X 
X 
X 
X 
X 
X 
A 
Health Outcomes Assessments 
• 
X 
X 
X 
X 
X 
X 
X 
A 
Adverse Events 
• 
X 
X 
X 
X 
X 
X 
X 
A 
Concomitant Medications 
• 
X 
X 
X 
X 
X 
X 
X 
A 
Dispense Seizure Diary 
X 
X 
X 
X 
X 
 
 
 
 
Document Seizures in Seizure Diary 
 
X 
X 
X 
X 
 
 
 
A 
Seizure Diary Review 
 
X 
X 
X 
X 
X 
 
Xg 
 


 
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Procedures 
Visit 1/ 
SCNa 
Visit 2 
Visit 
3 
Visit 
4 
Visits 5 
and 6 
Visit 7 
Post-1-year 
Visit 8 onwards  
EOS/ET 
Computer 
Systemsc 
Day 0 
Week 
1 
Mont
h 1 
Mont
h 3 
Months 6 
and 9 
Month 12 
Month 15 
onwardsb 
Dispense Study Drug 
X 
X 
X 
X 
X 
Xp 
X 
 
A 
Dispense Emergency Medication 
X 
 
 
 
 
 
 
 
 
Drug Accountability 
 
X 
X 
X 
X 
X 
X 
X 
A 
Dispense/Review MEC
X
X
X
X
X
X
X
X
Abbreviations:  A=Electronic Data Capture (Inform); B=Laboratory Information Management System (LIMS); C=Core Lab Over-Read; C-SSRS=Columbia Suicidality 
Severity Rating Scale; EOS=End of Study; ET=Early Termination; MADRS=Montgomery-Asberg Depression Rating Scale; NTx=N-telopeptides of type I collagen 
cross-links; SCN=Screening; 25-OHD=25-hydroxyvitamin D; TSH=thyroid stimulating hormone; PGI=Patient Global Impression; PTH=parathyroid hormone; 
QOLIE-31=31-Item Quality of Life in Epilepsy. 
a. 
Demographic information, medical history, psychiatric history, medication history, magnetic resonance imaging/computerized tomography scans, 
electroencephalogram data, HLA-B*1502 genotyping, and Hepatitis B/C screen results collected during the screening visit of Protocols 093-045 or 093-046 will 
apply for this study as well.   
b. 
Clinic visits to occur at intervals of 3 months during the post-1-year part. 
c. 
Letters in this column identify the computerized systems that will be used in this protocol (Appendix IX in protocol). 
d. 
The symbol “•” represents procedures performed at Visit 9 of Protocols 093-045 or 093-046, the results of which will apply to Visit 1 of the present study as well.  
These procedures do not have to be repeated.   
e. 
In street clothes without shoes and jacket/coat.   
f. 
Fasting labs. 
g. 
These assessments are not required to be performed if this visit falls in the post-1-year part of the study. 
h. 
If this visit falls in the post-1-year part of the study, this assessment may be performed only if clinically indicated (per Investigator judgement on a previously 
noted abnormality. 
i. 
Includes serum 25-OHD, PTH, osteocalcin, bone-specific alkaline phosphatase, and urinary NTx.   
j. 
At Visit 5 only. 
k. 
Every 6 months (i.e. Visits 7, 9, 11, 13, etc.). 
l. 
Only in subjects ≥18 years at time of signing informed consent in Protocols 093-045 or 093-046. 
m. Only for subjects who discontinue study during the post-1-year part of study. 
n. 
Fill out “since last visit” scale (Appendix VII in protocol).   
o. 
Only for subjects who discontinue study during the 1-year part of study. 
p. 
Only for subjects who continue into the post-1-year part of the study. 
 
 


 
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5.2. Efficacy Assessment and Endpoints 
5.2.1. Assessments
Each subject will be instructed to keep a seizure diary and record information on all 
seizures for the first one-year of the study starting from Visit 1 (Screening) and ending 
at Visit 7.  Subjects or caregivers can complete the study diary; however the person 
who maintains the diary should remain the same throughout the study.  Seizure 
occurrences since the previous visit, based on review of the seizure diary, will be 
recorded by date and seizure type on the eCRF.  At return visits 2 through 7, the 
seizure diary will be reviewed, and collected.   
The 31-Item Quality of Life in Epilepsy Scale (QOLIE-31)1 will be self-administered 
by only subjects who have completed 18 years of age at time of signing informed 
consent in Protocols 093-045 or 093-046.   
The Montgomery-Asberg Depression Rating Scale (MADRS)2 measures the severity 
of a subject’s depressive symptoms.  MADRS will be performed by a credentialed and 
trained MADRS rater.  
The Patient Global Impression (PGI) scale measures the patient impression of 
improvement in disease.  The PGI will be subject self-administered at all visits during 
the Post-1-Year Open-Label Period only.  The 5 individual items will be summarized 
with descriptive statistics for each Post-1-Year Open-Label Period visit.   
5.2.2. 1-Year Open-Label Period Efficacy Endpoints 
1. Time on eslicarbazepine acetate monotherapy  
Time on eslicarbazepine acetate monotherapy during 1-Year Open-Label Period will 
be calculated from the date of the first eslicarbazepine acetate monotherapy dose in 
protocol 093-045 or 093-046 (Visit 6/Week 8) to the last known dose of 
eslicarbazepine acetate monotherapy during 1-Year Open-Label Period as follows; 
a. For a subject who added a non-rescue AED during 1-Year Open-Label Period, 
Time on Monotherapy during 1-Year Open-Label Period is calculated as the 
date of start a non-rescue AED during 1 Year Open-Label Period minus the 
date of the first  monotherapy dose in protocol 093-045 or 093-046.    
b. For a subject who completed the 1-Year Open-Label Period, and did not add 
any non-rescue AED since the date of the first monotherapy dose in protocol 
093-045 or 093-046, Time on Monotherapy during 1-Year Open-Label Period 
is calculated as the date of the last known dose during 1-Year Open-Label 
Period, minus the date of the first monotherapy dose in protocol 093-045 or 
093-046, plus 1.  
c. For a subject who did not complete the 1-Year Open-Label Period, and did not 
add any non-rescue AED since the date of the first monotherapy dose in 
protocol 093-045 or 093-046, Time on Monotherapy during 1-Year Open-


 
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Label Period is calculated as the date of the known dose before the withdrawal 
during 1-Year Open-Label Period, minus the date of the first monotherapy 
dose in protocol 093-045 or 093-046, plus 1. 
2. Seizure frequency 
Seizure frequency from the subject’s 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 on study 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 
3. Relative change in seizure frequency from baseline 
Seizure frequency change from the baseline period will be evaluated by using SSF per 
4 weeks (28 days).  The baseline period is the period from Visit 1 to Visit 2 from 
Protocols 093-045 or 093-046. 
The relative (%) change in SSF for any interval of interest (including baseline) will be 
calculated as:  
(SSF during the interval of interest) –  
      (SSF during baseline period) 
x 100 
SSF during baseline period 
Further the relative change from baseline will be categorized into: 
 100% Decrease
 ≥ 75%  - < 100% Decrease 
 ≥ 50%  - < 75% Decrease 
 0% to < 50% Decrease 
 > 0%  to < 25% Increase 
 ≥25% to <50% increase 
 ≥50% to <100% increase 
 ≥100 % increase 
4. Responder rate 
Responder is defined as having a ≥50% reduction in SSF from baseline.  


 
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The proportion will be calculated as the number of responders divided by the total 
number of subjects in the ITT population entering the period of interest.   
5. Seizure-free  
Subjects who did not have any seizure as per the seizure diary during that time period 
will be deemed seizure free, for the corresponding interval of interest.  However, 
subjects who discontinue prior to Visit 7 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).  That is, subjects must 
complete each interval of interest without any seizures to be considered seizure-free 
for each interval of interest. 
The number and percent of seizure-free subjects will be presented for the interval of 
interest, for each interval the percent will be based out of the number of subjects in 
the ITT population entering each interval of interest.   
6. Seizure frequency by seizure type 
SSF will be calculated by seizure type using the same methods described in #2 of this 
section. 
7. Completion rates 
Study completion is defined as the proportion of subjects from the ITT population 
who completed the entire 1-Year Open-Label Period (Visit 1 to Visit 7). 
8. Treatment retention time (time to withdrawal due to lack of efficacy or adverse 
events).   
If a subject’s reason for withdrawal from 1-Year Open-Label Period included: 
withdrawal of consent, lost to follow-up, physician decision or other, then it will be 
assumed the subject terminated due to lack of efficacy. For subjects that discontinue 
due to adverse event or lack of efficacy, the treatment retention time during the 1-
Year Open-Label Period will be calculated as the date of last known dose during the 
1-Year Open-Label Period minus the date of the first dose of eslicarbazepine acetate 
monotherapy in protocol 093-045 or 093-046 (Visit 6/Week 8), plus 1.  The time may 
include taking eslicarbazepine acetate concomitantly with other AEDs.   
5.2.3. Post-1-Year Open-Label Period Endpoints 
1. Patient Global Impression  
PGI measures the effect of study drug by assessing patient overall impression on a 5-
point scale from 0 (best score) to 4 (worst score), including: 
• Very much improved 
• Improved 
• No change 
• Worse 


 
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• Very much worse 
PGI will be summarized from Visit 8 every three months during the Post-1-Year 
Open-Label Period until the End of Study or Early Termination Visit.     
2
Completion rates 
Completion rates for Post- 1-Year Open-Label Period will be defined as the proportion 
of subjects from the ITT population who had the reason for withdrawal from the Post-
1 Year Open-Label Period either “Sponsor terminates clinical study” or “Study drug 
became available in subject’s locale” from the end of study page in the CRF.  
3. Time on eslicarbazepine acetate monotherapy  
 Time on eslicarbazepine acetate monotherapy during Post1-Year Open-Label Period 
will be calculated from the date of the first eslicarbazepine acetate monotherapy dose 
in protocol 093-045 or 093-046(Visit 6/Week 8) to the last known dose of 
eslicarbazepine acetate monotherapy during Post-1-Year Open- Label Period  as 
follows; 
a. For a subject who added a non-rescue AED during Post-1-Year Open-Label 
Period, Time on Monotherapy during Post 1-Year Open-Label Period is 
calculated as the date of start a non-rescue AED during Post-1-Year Open-
Label Period minus the date of the first monotherapy dose in protocol 093-045 
or 093-046.    
b. For a subject who completed the Post-1-Year Open-Label Period, and did not 
add any non-rescue AED since the date of the first monotherapy dose in 
protocol 093-045 or 093-046, Time on Monotherapy during Post-1-Year 
Open-Label Period is calculated as the date of the last known dose during 
Post-1-Year Open-Label Period, minus the date of the first monotherapy dose 
in protocol 093-045 or 093-046, plus 1.  
c. For a subject who did not complete the Post-1Year Open-Label Period and did 
not add any non-rescue AED since the date of the first monotherapy dose in 
protocol 093-045 or 093-046, Time on Monotherapy during Post- 1-Year 
Open-Label Period is calculated as the date of the last known dose before the 
withdrawal during Post- 1-Year Open-Label Period, minus the date of the first 
monotherapy dose in protocol 093-045 or 093-046, plus 1. 
4. Treatment retention time 
If a subject’s reason for withdrawal from Post-1-Year Open-Label Period included: 
withdrawal of consent, lost to follow-up, physician decision or other, then it will be 
assumed the subject terminated due to lack of efficacy. For subjects that discontinue 
due to adverse event or lack of efficacy, the treatment retention time during Post-1-
Year Open-Label Period will be calculated as the date of last known dose during Post-
1-Year Open-Label Period minus the date of the first dose of eslicarbazepine acetate 
monotherapy in protocol 093-045 or 093-046 (Visit 6/Week 8), plus 1.  The time may 
include taking eslicarbazepine acetate concomitantly with other AEDs.   


 
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5.2.4. Entire Open-Label Period Endpoints 
1. Change in Quality of Life in Epilepsy 
The QOLIE-31 contains seven multi-item scales that assess the following health 
concepts:  emotional well-being, social functioning, energy/fatigue, cognitive 
functioning, seizure worry, medication effects, and overall quality of life.  The 
QOLIE-31 overall score is obtained by using a weighted average of the multi-item 
scale scores.  The QOLIE-31 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 1.   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 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 
If no score has been calculated for at least one of the 7 scales, the overall QOLIE-31 
score will not be calculated.  The change from baseline to each post-treatment 
assessment in QOLIE-31 overall score will also be calculated. 
Table 1:  QOLIE-31 Response Conversions 
Scale 
Response 
Formula 
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 


 
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    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 
    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 


 
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    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 
    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. 
Change in Quality of Life is defined as the change in QOLIE-31 total score from Visit 
2 (Day 0) of Protocols 093-045 or 093-046 to end of study treatment (ET/EOS).  
2. Change in Montgomery-Asberg Depression Rating Scale 
The MADRS measures the effect of study drug on depression severity by assessing 
the severity of 10 symptoms on a scale from 0 (best score) to 6 (worst score), 
including: 


 
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• Apparent sadness 
• Reported sadness 
• Inner tension 
• Reduced sleep 
• Reduced appetite 
• Lassitude 
• Concentration difficulties
• Suicidal thoughts 
• Inability to feel 
• Pessimistic thoughts 
The total score is defined as the sum of all individual item scores.  If one item is 
missing at a given visit, it will be replaced with the mean of the answers that are 
present.  If more than one item is missing at a given visit, no total score will be 
calculated.   
Change in MADRS total score will be summarized from Visit 2 (Day 0) of Protocols 
093-045 or 093-046 (baseline) to end of study treatment (ET/EOS). This analysis will 
be repeated for subjects with a MADRS score of ≥14 at screening visit (Visit 1) of the 
present study.   
5.3. Safety Assessments and Endpoints 
5.3.1. Safety Assessments 
Adverse events will be monitored throughout the study, starting at Visit 1.   
Clinical laboratory tests to be collected include:  serum chemistry, hematology, 
thyroid panel (free T3, free T4, and TSH), coagulation testing (prothrombin time 
[PT]/international normalized ration [INR] and partial thromboplastin time [PTT]), 
lipid panel (total cholesterol, high-density lipoprotein [HDL]-cholesterol, low-density 
lipoprotein [LDL]-cholesterol, and triglycerides), bone turnover markers (serum  
25-hydroxyvitamin D [25-OHD], parathyroid hormone [PTH], osteocalcin, 
bone-specific alkaline phosphatase, and urinary N-telopeptides of type I collagen 
cross-links [NTx]), and urinalysis.   
A 12-lead ECG collect ventricular heart rate, QT interval, P-R interval, QRS 
durations, R-R interval, and the QTc intervals corrected by Bazett (QTcB) and 
Fridericia (QTcF).   
Vital signs include standing and supine systolic and diastolic blood pressure, standing 
and supine heart rate, respiration rate, weight, and body temperature.  
Physical and neurological examinations will be conducted at Visit 1 and the End of 
Study or Early Termination Visit. 


 
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The C-SSRS is an instrument designed to systematically assess and track suicidal 
events (suicidal behavior and suicidal ideation) throughout the study.  The C-SSRS 
includes the following four sections: Suicidal Ideation, Intensity of Ideation, 
Suicidal Behavior and Actual Suicide Attempts.  The C-SSRS will be completed by 
the Investigator or Sub-Investigator (or qualified site personnel).   
5.3.2. Safety Endpoints 
Adverse Events 
All AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA), 
Version 13.1.   
Treatment-emergent adverse events (TEAEs) will be defined as:  
• AEs that occurred on or after the first dose of study drug during this protocol,   
• AEs with a missing start date and a stop date on or after the first dose of study 
drug during this protocol, or  
• AEs with both a missing start and stop date.   
Adverse events whose relationship is assessed as “not related” will be grouped as 
“unrelated.” Otherwise, adverse events assessed as “unlikely,” “possible,” “probable,” 
or “definite,” unknown or missing will be grouped as “potentially related.” Further, if 
a subject reports more than one AE within the same treatment regimen, system organ 
class (SOC) and preferred term (PT), and any are related, it will be summarized as 
related.   
If a subject has more than one occurrence of an event within a SOC and/or PT, the 
subject incidence summaries will count each subject only once within that SOC and/or 
PT.  In the case of more than one event within a SOC and/or PT, the event with the 
highest severity will be summarized in the by-severity summaries and the one with the 
strongest relationship will be summarized in the by-relationship summaries. 
TEAEs will be sorted by SOC in alphabetical order and then by PT sorted by 
decreasing frequency, with preferred terms with the same frequency sorted in 
alphabetical order. 
Clinical Laboratory Evaluation    
Observed values and change from baseline will be summarized for each visit, where 
change from baseline is the result of interest minus baseline value (Visit 2/Day 0 from 
protocol 093-045 or 093-046).  
Each laboratory result will be cross referenced with laboratory-provided normal 
reference ranges to determine whether the test result is below, within, or above the 
normal range.  Similarly, sponsor defined-potentially clinically significant (PCS) 
laboratory results will be identified using the criteria in Table 2.   


 
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Additionally, the number and percent of the subjects with normal baseline (Visit 
2/Day 0 from protocol 093-045 or 093-046) sodium levels reaching the following 
post-baseline blood sodium levels as below categories will be identified by time point: 
• ≤135 mEq/L and >130 mEq/L 
• ≤130 mEq/L and >125 mEq/L 
• ≤125 mEq/L 
• >10 mEq/L reduction (i.e. <-10 mEq/L) from baseline 
Table 2:  PCS Criteria for Laboratory Parameters 
Parameter Name
PCS Low 
PCS High 
Hematology 
 
 
WBC 
      ≤ 2.8 x 10^9/L 
      ≥ 16 x 10^9/L 
Neutrophils 
< 1.5 x10^9/L 
> 13.5 x10^9/L 
Lymphocytes 
N/A 
> 12 x10^9/L 
Monocytes 
N/A 
> 2.5 x10^9/L 
Eosinophils 
N/A 
> 1.6 k/mm3 
Basophils 
N/A 
> 1.6 k/mm3 
Hemoglobin for 
Females 
≤ 9.5 g/dL 
≥ 17.5 g/dL 
Hemoglobin for 
Males 
≤ 11.5 g/dL 
≥ 19.0 g/dL 
Hematocrit for 
Females 
≤ 32% 
≥ 54% 
Hematocrit for 
Males 
≤ 37% 
≥ 60% 
RBC 
      ≤ 3.5 x 10^12/L 
      ≥ 6.4 x 10^12/L 
Platelet Count 
≤ 75 x 10^9/L 
      ≥ 700 x 10^9/L 
Chemistry 
 
 
Sodium 
≤ 126 mEq/L 
≥ 156 mEq/L 
Potassium 
≤ 3 mEq/L 
≥ 6 mEq/L 
Chloride 
≤ 90 mEq/L 
≥ 118 mEq/L 
Calcium 
< 8.2 mg/dL 
≥ 12 mg/dL 
AST 
N/A 
≥ 3 x ULN 
ALT 
N/A 
≥ 3 x ULN 
Alkaline 
phosphatase 
N/A 
≥ 3 x ULN 
Creatinine 
N/A 
≥ 2 mg/dL 
BUN 
N/A 
≥ 30 mg/dL 
Total bilirubin
N/A
≥ 2 mg/dL
Total protein 
≤ 4.5 g/dL 
≥ 10 g/dL 
Albumin 
≤ 2.5 g/dL 
N/A 
Glucose 
≤ 40 mg/dL 
≥ 175 mg/dL 
Creatinine  
Phosphokinase 
N/A 
> 2.5 x ULN 


 
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Phosphate 
< 2.0 mg/dL 
> 5.3 mg/dL 
HDL-Cholesterol 
< 30 mg/dL 
N/A 
LDL-Cholesterol 
N/A 
> 160 mg/dL 
Total Cholesterol 
> 300 mg/dL 
N/A 
Triglycerides 
N/A 
> 2.5 x ULN 
Blood Coagulation 
 
 
aPTT 
N/A 
> 1.5 ULN 
INR
N/A
> 1.5 ULN
Thyroid Function 
 
 
Free T3 
< 0.20 ng/dL 
> 0.415 ng/dL 
Free T4 
< 0.75 ng/dL 
> 1.75 ng/dL 
12-Lead ECG 
            Observed values and change from baseline will be summarized for each visit, where 
            change from baselineis the result of interest minus the baseline result (Visit 2 from  
            protocol 093- 045 or 093-046).   
            The number and percentage of subjects with QTc-F values in the following categories 
            will be identified:  
• QTc-F >500 ms at any postdose time point not present at baseline  
• QTc-F >480 ms at any postdose time point not present at baseline  
• QTc-F >450 ms at any postdose time point not present at baseline  
• Change from baseline in QTc-F ≥60 ms for at least 1 postdose measurement  
• Change from baseline in QTc-F ≥30 ms for at least 1 postdose measurement, 
but <60 ms for all postdose measurements.       
            This categorical analysis will be also performed for QTc-B.  
 
         The incidence of specific ECG abnormalities will also be identified for the following   
         categories: 
• Overall abnormalities 
• Rhythm abnormalities 
• Conduction abnormalities 
• Morphology abnormalities 
• Myocardial infarction 
• Presence of ST Segment abnormalities 
• Presence of T wave abnormalities 
• Presence of U wave abnormalities 
Vital Signs 
Observed values and change from baseline will be summarized for each visit, where 
change from baseline is the result of interest minus the baseline result (Visit 2 from 
protocol 093-045 or 093-046).   
In addition, subjects meeting the sponsor defined vital sign PCS criteria (Table 3) will 
be identified.  


 
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A vital sign value is considered PCS low if it is below the specified low limit and it 
decreases from baseline more than the specified decrease from baseline limit.  A vital 
sign value is considered PCS high if it is higher than the specified high limit and it 
increases from baseline more than the specified increase from baseline limit. 
             Table 3:  PCS Criteria for Vital Signs 
Parameter Name 
Low 
Decrease 
from 
Baseline 
 
High 
Increase 
from 
Baseline 
Supine Systolic 
BP 
< 90 mm Hg 
≥ 20 mm Hg 
> 180 mm 
Hg 
≥ 20 mm Hg 
Supine Diastolic 
BP 
< 50 mm Hg
≥ 15 mm Hg
> 105 mm 
Hg 
≥ 15 mm Hg
Supine Heart Rate 
< 50 bpm 
≥ 15 bpm 
> 120 bpm 
≥ 25 bpm 
Weight 
N/A 
≥ 7%
N/A 
≥ 7% 
Body Weights 
Observed weight values and change from baseline will be summarized for each visit, 
where change from baseline is the weight at the visit of interest minus the baseline 
weight (Visit 2 from protocol 093-045 or 093-046). Subjects with a weight change of 
≥7% will be identified at each visit by dividing the change from baseline weight, by 
the baseline weight, and multiplying by 100.                 
 Orthostatic Effects 
The number and percentage of subjects who experienced orthostatic hypotension and 
orthostatic tachycardia will be summarized. Orthostatic effects can be determined for a 
vital sign, by examining the difference between positions. 
(Standing result during the interval of interest)- (Supine result during the interval of 
interest) 
Orthostatic hypotension is having a difference of ≤ -20 mmHg in systolic or ≤ -10 
mmHg in diastolic blood pressure.  Orthostatic tachycardia will be defined as a 
difference in heart rate ≥ 20 beats per minute and the standing heart rate >100 beats 
per minute  after the subject was standing for at least 2-4 minutes. 
Other Safety Assessments 
Physical and neurological examinations performed at Visit 1 of protocols 093-045 or 
093-046 will apply to Visits 1 (Screening) of the present study.   
Columbia-Suicide Severity Rating Scale (C-SSRS) 
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, 


 
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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. Suicidal ideation is rated 
on a 6-point scale from 0=’No ideation present’ to 5=’Active ideation with plan and 
intent’.  A score of 4 or 5 on this scale indicates serious suicidal ideation.   
Suicidality is defined as having at least one occurrence of suicidal ideation or at least 
one occurrence of suicidal behavior during the assessment period. 
Concomitant medications 
All medications will be coded using WHO Drug, version 01Jun2009. The number and 
percentage of subjects using each concomitant medication will be summarized 
according to the WHO DRUG Class and preferred term (PT).  Subjects with multiple 
uses of a concomitant medication will be counted once for a given WHO Drug Class 
and PT. Prior medications are defined as any medication with an end date before the 
first dose of study medication. Concomitant medications are defined as medications 
present on or after the first dose of study medication.  
6. Statistical Methods 
6.1 General Methodology 
All statistical procedures will be performed using SAS Version 9.2 or higher. 
Continuous variables, including those assessed on a discrete scale, will be summarized 
using descriptive statistics, including the number of subjects, mean, standard 
deviation, minimum, 25th percentile, median, 75th percentile, and maximum.  For 
categorical variables, summaries will include counts of subjects and percentages. 
Baseline  
Change in seizure related efficacy parameters will be calculated with reference to the 
baseline period defined as the baseline period (From Visit 1 to Visit 2) from protocol 
093-045 and 093-046.  The change in QOLIE, MADRS and safety parameters will be 
calculated with reference to the baseline as Day 0 (Visit 2) for protocol 093-045 and 
093-046.  
3-month visit windows 
There are four 3-month intervals for the 1-Year Open-Label Period.  The first window 
is defined as ≥Visit 1and <Visit 4, the second window is ≥Visit 4 and <Visit 5, the 
third window is ≥Visit 5 and <Visit 6 and the fourth window is ≥Visit 6 and <Visit 7).  
This 3-month interval will used to summarize seizure related efficacy data. 
6.2 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 


 
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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 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 for each interval up to the last interval 
where the subject had data.  The last interval standardized seizure frequency will be 
computed based on available data prior to dropout. 
For QOLIE31 and MADRS, if only one item is missing, it will be imputed by the 
average of other items for calculating the total score (See Section 5.2.4: 1 and 2). 
6.3 Interim Analyses and Data Monitoring 
There will be no interim analysis or formal data monitoring during this study. 
6.4 Multiple Comparisons/Multiplicity 
             There will be no multiple comparison/multiplicity for this study.  
6.5 Examination of Subgroups 
To examine potential differences in the outcomes by the subgroups as below, the 
following data will be summarized separately by the subgroups: SSF, Relative change 
(%) from baseline in SSF, responders, adverse events, and PCS laboratory parameters.              
Demographic subgroups 
• Age (<18, 18-65, >65 years old) 
• Gender (Male, Female) 
• Race (White, Black or African American, Asian, Other) 
Baseline AEDs subgroups
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 into the titration period from protocol 093-045 
or 093-045. Subjects may appear in multiple AED use subgroups.  
• Number of baseline AEDs (0, 1, 2, or more AEDs)  
• Baseline AEDs 
 Use of carbamazepine as baseline AED (yes/no)  
 Use of oxcarbazepine as baseline AED (yes/no)  
 Use of carbamazepine or oxcarbazepine as baseline AED (yes/no)  
 Use of lamotrigine as baseline AED (yes/no) 


 
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 Additional individual baseline AEDs that occur in ≥ 15% of the subjects 
(namely, levetiracetam, and valproic acid)  
Seizure subgroups 
             Seizure type (simple partial, complex partial, partial evolving to secondarily 
             generalized seizures) 
 
Actual Monotherapy Used subgroup 
 
The subjects who started on actual monotherapy (i.e. 10 weeks double-blind 
monotherapy from protocol 093-045 or 093-046), entered this study and did not add 
any non-rescue AED during the study participation will be defined as Actual 
Monotherapy Used subgroup.   
 
For those subjects, the following data including ESL exposure and compliance, 
concomitant medication, SSF, relative (%) change from baseline in SSF, responders, 
TEAE, SAE, Death, TEAE leading to discontinuation, and minimum post-dose 
sodium level change from baseline will be summarized. 
7. Statistical Analysis  
7.1 Analysis Populations 
The intent-to-treat (ITT) population will consist of all subjects who have taken any 
open-label study medication.  The ITT population will be used for all safety and all 
efficacy analyses. 
The per-protocol (PP) population will consist of all subjects in the ITT population who 
did not have any important protocol deviations. The per-protocol population will be 
used in an additional analysis of the efficacy endpoints and subject demographics and 
baseline characteristics. 
7.2 Disposition of Subjects 
The number and percentage of subjects who entered 1-Year Open-Label Period, who 
completed the 1-Year Open-Label Period, who discontinued during 1-year Open-
Label Period (including reasons for discontinuations), who completed 1-Year Open-
Label period but did not enter the Post-1-Year Open-Label Period, entered Post-1-
Year Open-Label Period, 
and 
discontinued 
early 
(including 
reasons 
for 
discontinuations) for Post-1-Year Open-Label Period, and who completed Post-1-Year 
Open-Label Period will be summarized. The number and percentage of subjects who 
were in actual monotherapy used subgroup and PP population will be also summarized 
respectively. 
Subject disposition will be summarized for the ITT population.  
Listing of subject disposition will be provided. 


 
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7.3 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 during open-label treatment 
period  
• Developed withdrawal criteria but were not withdrawn  
The potentially important protocol deviations will be identified shortly before database 
lock, either programmatically (e.g., inclusion/exclusion criteria violations) or through 
review of data listings (e.g., investigator comments, concomitant medications).  
Appropriate personnel (including, at a minimum, a medical director, and a 
biostatistician) will review the list of potential IPDs to identify which will be 
considered IPDs.  The final list of IPDs will be documented and used to generate a 
data listing.  The number and percentage of subjects with IPDs will be summarized by 
the categories above.   
Listing of IPDs will be provided. In addition, subject inclusion and exclusion criteria 
will be provided. 
7.4 Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics at Screening/Visit 1 from Protocol 093-045 
or 093-046 will be summarized including  age, gender, race, ethnicity, country, height,  
weight, and BMI (continuous and categorized as <18, 18-30, >30 kg/m2), concomitant 
AEDs, country, region (US/Non-US), as well as disease conditions, will be 
summarized using descriptive statistics.   
Demographic and baseline characteristics, Medical history, and Epilepsy history will 
be summarized for the ITT population.  
Listing of demographic and baseline characteristic data, medical history, and epilepsy 
history will be provided.  
7.5 Extent of Exposure and Compliance 
The extent of exposure will be summarized descriptively: it will be calculated as the 
date of last reported dose minus the first dose date of 093-050 study, ignoring missing 
days plus 1. If the day of first dose of study drug is unknown, this will be set to the 
first dispensing date. If the day of last dose of study drug is unknown, then this will be 
set to the day of last contact. 
Extent of exposure will be summarized by the following mean daily dose categories: 
• ESL < 1000 mg  
• ESL 1000 mg – <1400 mg  


 
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• ESL 1400 mg – <2000 mg  
• ESL ≥ 2000 mg  
• Total ESL  
Duration of Exposure: 
The frequency of duration of exposure will be summarized using the following 
categories: 
• 1-7 Days 
• > 1-2 Weeks 
• > 2-4 Weeks 
• > 4-6 Weeks 
• > 6-8 Weeks 
• > 8-10 Weeks 
• >10-12 Weeks 
• > 12-14 Weeks   
• 
> 14-16 Weeks 
• > 16-18 Weeks 
• > 18-20 Weeks 
• > 20-26 Weeks 
• > 26-52 Weeks   
• > 52-104  Weeks  
• > 104 Weeks (24 Months) 
Subject-years of exposure will be calculated by summing the overall exposure for each 
subject within the dose group dividing by 365.25. 
The number of tablets taken per subject will be summarized as a continuous variable. 
The total number of tablets taken will be determined by subtracting the total number 
of tablets returned and reported lost from the total number of tablets dispensed.   
Continuous summaries of mean daily dose will also be presented.  The mean daily 
dose level (mg) of ESL will be calculated as the total number of tablets taken within 
each treatment interval multiplied by the tablet strength, and then divided by the 
duration (in days) of treatment within the treatment interval. The overall mean daily 
dose will be calculated as the weighted average of the treatment intervals (i.e., the sum 
of the non-missing mean daily doses for each treatment interval multiplied by their 
respective number of days in the interval, divided by the total number of days in the 


 
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intervals with non-missing mean daily doses). 
Descriptive statistics will be used to summarize percent compliance.  Further, the 
number and percent of subjects that are <80%, 80-120% or >120% will be displayed.   
Percent compliance will be derived as the number of tablets taken divided by the 
number of tablets that should have been taken, expressed as a percent.   
Listing of subject treatment exposure and compliance will be provided. In addition, 
listing of study drug dosing and study drug accountability including number of tablets 
dispensed, returned, lost/missing, taken will be provided. 
7.6 Efficacy Analyses  
ITT population will be used for all the efficacy analyses. For the analysis of seizure 
data, listing of seizure symptoms, seizure diary, and SSF and related derived 
parameters will be provided.  
Time on eslicarbazepine acetate monotherapy   
Kaplan Meier methods will be used to estimate the median time (and 95% CI) on 
eslicarbazepine acetate monotherapy for both 1-Year Open-Label Period and Post-1-
Year Open-Label Period.   
 
For the 1-Year Open-Label Period, time on monotherapy as defined in Section 5.2.2 
will be used for analysis. Subjects who were still taking only eslicarbazepine acetate 
as monotherapy at the end of the 1-Year Open-Label Period of study will be censored 
at the last dose of the 1-Year Open-Label Period. Subjects who withdrew during the 
1-Year Open-Label Period will also be censored at the time of the last known dose 
before the withdrawal. Subject who added a non-rescue AED will be an event on the 
date of the start AED during 1-Year Open-Label Period. 
  
For the Post-1-Year Open-Label Period, time on monotherapy as defined in Section 
5.2.3 will be used for analysis. Subjects who were still taking only eslicarbazepine 
acetate as monotherapy at the end of the Post-1-Year Open-Label Period will be 
censored at the last dose of the Post-1-Year Open-Label Period. Subjects who 
withdrew during the Post-1-Year Open-Label Period will also be censored at the time 
of the last known dose before the withdrawal. Subject who added a non-rescue AED 
will be an event on the date of the start AED during Post-1-Year Open-Label Period. 
 
Subjects who never started the monotherapy treatment period in protocol 093-045 or 
093-046 will not be included in this analysis. Change in dosage levels from protocol 
093-045 or 093-046, dosage changes during protocol 093-050, and the time gap 
between the parent studies and the extension study will be ignored.  
Seizure standard frequency (SSF)  
Descriptive statistics will summarize the SSF for 1 week, 1 month, each 3 month visit 
window of time, overall, and by the following subgroups:  number of baseline AEDs, 


 
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and baseline AED medications, and seizure type. 
Relative (%) change from baseline in SSF 
Relative (%) change from baseline in SSF will be summarized descriptively for 1 
week, 1 month, each 3-month visit window, overall, and by the following subgroups:  
number of baseline AEDs, and baseline AED medications, seizure type. The number 
and percentage of subjects with the category in Section 5.2.2 will also be presented.    
Responder rate 
The number and proportion (%) of responders with 95% confidence intervals (using 
binomial methods) will be presented for 1 week, 1 month, each 3-month visit window, 
overall, and by the following subgroups:  number of baseline AEDs, and baseline 
AED medications. 
Seizure-free 
The number and proportion (%) of subjects that are seizure-free with 95% confidence 
intervals (using binomial methods) will be presented for 1 week, 1 month, each 3-
month visit window and overall.  
Completion rate 
The number and proportion (%) of subjects completing the 1-Year Open-Label Period 
and Post-1-Year Open-Label Period will be provided along with a 95% confidence 
interval (using binomial methods).   
Treatment retention 
Kaplan Meier methods will be used to estimate the median retention time (and 95% 
CI) on eslicarbazepine acetate for subjects who discontinued early due to adverse 
event(s) or lack of efficacy for both 1-Year Open-Label Period and Post-1-Year 
Open-Label Period.   
For 1-Year Open-Label Period, subjects who discontinued the study not due to those 
reasons (i.e. protocol deviation) as defined in Section 5.2.2 will be censored at the 
date of the last known dose during 1-Year Open-Label Period. Subjects who were still 
taking eslicarbazepine acetate at the end of the 1-Year Open-Label Period of study 
will be censored at the last dose of the 1-Year Open-Label Period. 
 
For Post-1-Year Open-Label Period, subjects who discontinued the study not due to 
those reasons (i.e. protocol deviation, study drug became available in subject’s locale, 
and sponsor terminates clinical study) as defined in Section 5.2.3 will be censored at 
the date of the last known dose during Post-1-Year Open-Label Period. Subjects who 
were still taking eslicarbazepine acetate at the end of the Post-1-Year Open-Label 
Period of study will be censored at the last dose of the Post-1-Year Open-Label 
Period. 


 
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Change in Quality of Life in Epilepsy (QOLIE-31)  
 Values and change from baseline (Visit 2, Day 0 from protocol 093-045 or 093-046) 
in the seven individual items, overall score, and global assessment will be summarized 
with descriptive statistics for each visit. A listing of subjects with QOLIE-31 
assessments will be provided. 
Change in Montgomary-Asberg Depression Rating Scale (MADRS)  
The total MADRS score and the 10 individual items will be summarized descriptively 
for each evaluation visit, along with the change from baseline (Visit 2, Day 0 from 
protocol 093-045 or 093-046). 
In addition, this analysis will be repeated for those subjects with a MADRS score of 
≥14 at screening (Visit 1) of this study. A listing of subjects with MARDS 
assessments will be provided. 
Patient Global Impression (PGI) 
The total PGI score and the 5 individual items will be summarized descriptively from 
Visit 8 every three months during the Post-1-Year Open-Label Period, until the End of 
Study or Early Termination Visit.   
Listing of Patient Global Impression (PGI) will be provided. 
7.7 Safety Analyses  
Safety outcomes will be analyzed descriptively.  Safety variables will include adverse 
events, vital sign measurements, orthostatic effects, clinical laboratory evaluations 
(serum chemistry, hematology, and urinalysis), thyroid function, lipid levels, 
coagulation testing, and bone turnover markers, body weight, blood sodium levels, 
ECG readings, and C-SSRS. 
7.7.1 Adverse Events 
The following TEAEs will be summarized by MedDRA SOC and PT:  
• All AEs (including number of events and subject incidence)  
• AEs by severity (mild, moderate, severe)  
• All serious adverse events (SAE)  
• All AEs by relationship to treatment (unrelated, or potentially related) 
• AEs leading to death 
• AEs leading to discontinuation  
All above AEs and the AE subgroup analyses in Section 6.5 will be summarized for 
the three periods as below. 
• Year Open-Label Period 
• Post-1-Year Open-Label Period 
• Combined 1-Year Open-Label Period and Post-1-Year Open-Label Period 


 
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A listing of AEs, serious AEs, and AEs leading to discontinuation or death will be 
presented as appropriate. 
7.7.2 Clinical Laboratory Evaluation 
Descriptive statistics for test results and change from baseline (Visit 2/Day 0 from 
protocol 093-045 or 093-046) will be displayed at each scheduled visit (i.e. Visit 3-
Visit 7) for each continuous laboratory parameter.   
The normal reference ranges for laboratory tests will be used to determine whether the 
laboratory test value is below, within, or above the normal range. Shifts from baseline 
to each visit will be produced to show the percentage of subjects with laboratory test 
values below, within, and above the normal range.  The percentage will be based on 
the number of subjects with a baseline result and at least one post-baseline result for 
each parameter.   
Clinical significance of post-baseline abnormally low and high values will be 
summarized for each lab parameters.  
A listing of urine drug screen and serum pregnancy test results will also be provided.   
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 PCS criteria will be summarized by 
overall, and by the subgroups including age group, race, gender, number of baseline 
AED and baseline AEDs. 
The listing of the Special Interest of Elevation defined as elevation of any post-dose 
AST or ALT > 3x ULN will be provided.  
Listing of clinical laboratory measurements (hematology, serum chemistry, urinalysis, 
blood coagulation, bone turnover marker measurements) will be provided.  
In addition, listing of clinically significant out of range laboratory measurements, 
laboratory comments, and listing of subjects meeting any of the PCS lab criteria will 
be provided. 
In addition to continuous summaries of blood sodium levels, the number and 
percentage of subjects with normal baseline sodium level and a post- baseline level 
≤135 mEq /L but >130 mEq /L, ≤130 mEq /L but >125 mEq /L, ≤125 mEq /L, and 
>10 mEq/L reduction (i.e. <-10 mEq/L) from baseline will be summarized by time 
point and overall post-baseline.  
Above blood sodium levels will be also summarized by baseline AED and for actual 
monotherapy used subgroup. 
7.7.3 ECG Evaluations 
Descriptive statistics for each parameter and change from baseline (from protocol 
093-045 or 093-046) values will be displayed at each scheduled visit (i.e. Visit 3-Visit 
7) for each ECG parameter.   


 
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Sunovion Inc. 
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Author: 
Hanaa Girgis 
Version: Final  
Version Date:  19May2017 
Copyright © 2010 Quintiles Transnational Corp.  All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp.  Unauthorized use, disclosure 
or reproduction is strictly prohibited. 
The number and percentage of subjects with QTc-F values in the categories as defined 
in Section 5.3.2 will be summarized. 
•
QTc-F >500 ms at any post-baseline time point not present at baseline
• QTcF >480 ms at any post-baseline timepoint not present at baseline 
• QTc-F >450 ms at any post-baseline time point not present at baseline 
• Change from baseline in QTc-F ≥60 ms for at least 1 post-baseline 
measurement  
• Change from baseline in QTc-F ≥30 ms for at least 1 post-baseline 
measurement, but <60 ms for all post-baseline measurements 
This categorical analysis will be also performed for QTc-B. 
 
The number and percentage of subjects with ECG abnormalities will be presented in 
the categories of overall, rhythm, conduction, morphology, myocardial infarction and 
the presence of ST, T, and U wave abnormalities.  
Listing of 12-Lead ECG Measurements, Abnormality Findings and Overall 
Interpretation, and 12-Lead ECG collections will be provided.  
7.7.4 Vital Signs 
Observed values and change from baseline period (Visit 1-2 in 093-045 or 093-046) in 
each vital sign parameter will be summarized at baseline and by visit.  A listing of 
vital signs will be provided.  Height will only be summarized at baseline and end of 
study. 
In addition, the number and percentage of subjects meeting sponsor defined PCS vital 
sign values (outlined in Table 3) will be summarized for 1-Year Open-Label Period 
and Post-1-Year Open-Label Period. 
In addition a listing of subjects meeting any of the PCS vital signs criteria defined by 
the sponsor will be provided.  
7.7.5 Orthostatic Effects 
The number and percentage of subjects who had orthostatic effects (hypertension and 
tachycardia in Section 5.3.2) will be summarized from Visit 1 (Day 0) until the End of 
Study or Early Termination Visit for the ITT population.  
7.7.6 Physical and Neurological Examinations 
The physical and neurological examinations of subjects at beginning of the study and 
end of study will be summarized by presenting the number and percentage of subjects 
with normal and abnormal findings in each body area (skin/extremities, EENT, 
head/neck, etc.) for the ITT population.   


 
Statistical Analysis Plan  
Sunovion Inc. 
093-050 
Page 34 of 34 
 
Author: 
Hanaa Girgis 
Version: Final  
Version Date:  19May2017 
Copyright © 2010 Quintiles Transnational Corp.  All rights reserved. 
The contents of this document are confidential and proprietary to Quintiles Transnational Corp.  Unauthorized use, disclosure 
or reproduction is strictly prohibited. 
Listing of physical examination findings and neurological examination findings will 
be provided.  
7.7.7 Concomitant Medication 
Other than the study drug, any medication taken by subjects during the course of the 
study will be considered concomitant.  The number and percentage of subjects using 
each concomitant medication will be summarized according to the WHO Drug Class 
and preferred term for concomitant AED and non-AED medication separately.  
Subjects with multiple uses of a concomitant medication will be counted once for a 
given WHO Drug Class and Preferred term.  
Listing of concomitant AED, non-AED medications, prior medication, and rescue and 
emrgency medication will also be presented. 
7.7.8 Columbia-Suicide Severity Rating Scale (C-SSRS) 
Results from the C-SSRS assessments will be summarized by presenting the number 
and percentage of subjects with any suicidality, suicidal behavior and type of 
behavior, and any suicidal ideation and type of ideation.  
Shifts in suicidal ideation from baseline to worst post-baseline result will be 
presented. Worsening ideation is reflected in shifts from lower to higher values. 
C-SSRS will be summarized from Visit 1 until the End of Study or Early Termination 
Visit for the ITT population.  
Listing of the C-SSRS assessments will also be presented. 
8. References 
 
1 Cramer, JA, Perrine K, Devinsky O, Bryant-Comstock L, Meador K, Hermann BP.  
Development and cross-cultural translation of a 31-item quality of life questionnaire 
(QOLIE-31).  Epilepsia.  1998; 39:81-88. 
 
 2. Montgomery SA, Asberg M.  A new depression scale designed to be sensitive to 
change.  Br J Psychiatry.  1979; 134:382-389.