Clinical trial NCT00310388
Conditions: Epilepsy
Keywords: Partial Seizures Epilepsy RTG115097 Complex Partial Seizures Anticonvulsant Potassium Channels Epilepsies, Partial
Sponsor: GlaxoSmithKline
Start date: 2006-07-05; Completion date: 2018-05-24
Enrollment: 376 participants; Allocation: NON_RANDOMIZED; Intervention model: SINGLE_GROUP

Brief summary:
This Phase 3 trial is an open-label extension study of the placebo-controlled, double-blind VRX-RET-E22-302 trial. Patients who have completed the VRX-RET-E22-302 trial and who meet inclusion and exclusion criteria will be treated with 600-1200 mg/day of retigabine as an adjunct therapy to their current antiepileptic drugs (AEDs) or vagal nerve stimulation. Treatment will be continued until the subject withdraws from the study or until the program is discontinued. Patients will be recruited from 55-60 sites in Europe, Israel, Australia, and South Africa. The primary objective of the study is to evaluate the safety and tolerability of long-term therapy with retigabine administered as adjunctive therapy in adult epilepsy patients with partial-onset seizures, who completed the double-blind Study VRX-RET-E22-302. Secondary objectives are: to evaluate efficacy of long-term treatment with retigabine and patient quality of life and to evaluate whether retinal pigmentation, unexplained vision loss, pigmentation of non-retinal ocular tissue, and discoloration of nails, lips, skin or mucosa change over time after discontinuation of retigabine.

Detailed description:
This Phase 3 trial is an open-label extension study of the placebo-controlled, double-blind VRX-RET-E22-302 trial. Patients who have completed the VRX-RET-E22-302 trial and who meet inclusion and exclusion criteria will be treated with 600-1200 mg/day of retigabine as an adjunct therapy to their current antiepileptic drugs (AEDs) or vagal nerve stimulation. Treatment will be continued until retigabine is commercially available, or until the program is discontinued. Patients will be recruited from 55-60 sites in Europe, Israel, Australia, and South Africa. The safety and tolerability of long-term therapy with retigabine administered as adjunctive therapy in adult epilepsy patients with partial-onset seizures will be evaluated. In addition, the efficacy of long-term treatment with retigabine and patient quality of life will be assessed.

Arms: arm 1: Retigabine (Ezogabine): all subjects
Interventions: intervention 1: Retigabine (INN), Ezogabine (USAN)
Intervention descriptions: intervention 1: Film-coated tablets containing 50 mg, 100 mg, or 300 mg of retigabine per tablet. Dosage and frequency will be specific to each patient so long as the patients receives between 600 and 1200 mg of retigabine per day. The duration will be until the completion of the trial, or until the patient withdraws from the trial.

Protocol documents:
Prot_000.pdf: 
16 
Appendices 
 
16.1 
Study Information 
 
16.1.1 Protocol and Protocol Amendments 
 
The following protocols, amendments, and amendment summaries are provided: 
Protocol Amendment 2 
14 Aug 2008 
Protocol Amendment 1 Addendum 2 (for France) 
08 Nov 2007 
Protocol Amendment 1 Addendum 1  
     (Administrative Change) 
20 Jul 2007 
Protocol Amendment 1 
02 July 2007 
Protocol Addendum 3 (for Germany – 
     additional changes) 
01 Nov 2006 
Protocol Addendum 2 (for Hungary) 
28 Jul 2006 
Protocol Addendum 1 (for Germany) 
06 Jul 2006 
Original Protocol 
10 Feb 2006 
 
VRX-RET-E22-304 Clinical Study Report 
 
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Retigabine Protocol VRX-RET-E22-304, Amendment 1 
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Open-Label Phase 3 Extension Study 
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Confidential 
This document contains confidential information, which should not be copied, referred to, released or 
published without written approval from Valeant Pharmaceuticals, North America.  
 
 
 
 
 
Clinical Study Protocol 
Retigabine 
 
A multicenter, open-label, long-term, safety, 
tolerability and efficacy study of retigabine in adult 
epilepsy patients with partial-onset seizures 
(Extension of Study VRX-RET-E22-302) 
 
Protocol Number VRX-RET-E22-304 
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published without written approval from Valeant Pharmaceuticals, North America.  
 
 
 
 
 
1. TITLE PAGE 
STUDY TITLE: 
A multicenter, open-label, long-term, 
safety, tolerability and efficacy study of 
retigabine in adult epilepsy patients with 
partial-onset seizures (Extension of 
Study VRX-RET-E22-302) 
INVESTIGATIONAL PRODUCT: 
Retigabine 
IND NUMBER: 
53,950 
PROTOCOL NUMBER: 
VRX-RET-E22-304, Amendment 1 
PHASE: 
3 
SPONSOR: 
Valeant Pharmaceuticals, North America 
One Enterprise 
Aliso Viejo, CA 92656 USA 
Main Office: 
 
FAX: 
 
CONTRACT RESEARCH 
ORGANIZATION (CRO): 
Quintiles, Inc.  
5927 South Miami Blvd. 
Morrisville, NC 27560 
CRO MEDICAL MONITOR: 
 MD 
Quintiles Hungary, Ltd 
Budafoki ut 91-93 
H-1117 Budapest 
Tel: 
 
Facsimile: 
 
COUNTRIES:  
Western, Central and Eastern Europe, 
Australia, Israel, and South Africa 
 
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2. PROTOCOL SIGN-OFF SHEET 
PROTOCOL TITLE: 
A multicenter, open-label, long-term, safety, 
tolerability and efficacy study of retigabine in adult 
epilepsy patients with partial-onset seizures 
(Extension of Study VRX-RET-E22-302) 
PROTOCOL NUMBER: 
VRX-RET-E22-304 
VERSION: 
July 2, 2007 
 
Reviewed and Approved by: 
 
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3. SUMMARY OF REVISIONS 
SECTION: 
1. TITLE PAGE, section Sponsor 
REVISION: 
Amended to read (see bold text)  
Valeant Research and Developemnt Pharmaceuticals, North America 
3300 Hyland Ave. One Enterprise 
Costa Mesa  Aliso Viejo, CA 926256 USA 
Main office. 
 
  
Facsimile: 
  
 
RATIONALE: 
To provide new address and contact information of Sponsor.  
 
 
SECTION: 
1.  TITLE PAGE, section CRO Medical Monitor 
REVISION: 
Amended to read (see bold text)  
  
 MD 
Quintiles  GmbH  Hungary Ltd. 
Hugenottanelee 167  Budafoki ut 91-93 
D-63263 Neu-Isenberg  H-1117 Budapest 
Tel. 
 Ext. 
  
  
Facsimile: 
  
 
RATIONALE: 
To provide new address and contact information of CRO Medical Monitor.  
 
SECTION: 
3.  SUMMARY OF REVISIONS 
 
REVISION: 
Added new Section 3. SUMMARY OF REVISIONS.  All sections after this 
have been renumbered.  
   
RATIONALE: 
This section was added to describe what has been modified in Amendment 
1 of the VRX-RET-E22-304 protocol.  
SECTION: 
Throughout the protocol 
REVISION: 
IS: ….Valeant Pharmaceuticals, North America… 
WAS: …Valeant Research and Development… 
RATIONALE: 
Due to company restructuring, the legal entity known as Valeant Research & 
Development has been folded into Valeant Pharmaceuticals, North America. 
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6.   STUDY SYNOPSIS, subsection “KEY INCLUSION CRITERIA” 
and 
9.5  Inclusion Criteria, subsection 3 
 
REVISION: 
Amended to read (see bold text): 
 …females [deleted] had to shall have a negative [added] urine pregnancy 
test at Visit 0, which will be confirmed by the serum β-HCG pregnancy 
test at the last visit [added] (Visit 11) of the Transition phase of Study VRX-
RET-E22-302… 
   
RATIONALE: 
The urine pregnancy test has been added to provide immediate confirmation 
regarding non-pregnant eligibility requirements for female patients of child-
bearing potential.  
  
SECTION: 
6.   STUDY SYNOPSIS, subsection, “KEY EXCLUSION CRITERIA”  
and 
9.6  Exclusion Criteria  
REVISION: 
[Added] 
4.   Female patient who has a positive pregnancy test at any time 
during the study.   
 
RATIONALE: 
To more clearly define pregnancy exclusion criteria for female subjects 
participating in the VRX-RET-E22-304 trial.   
 
SECTION: 
9.7.1  Dosage Schedule and Mode of Administration  
REVISION: 
[Added] 
At the investigator’s discretion, patients may also start with another 
dose regimen that can be either BID or TID, and is not required to be 
equally distributed throughout the day (e.g., if a patient experiences 
somnolence and the investigator decides to dose the patient higher in 
the evening) as long as the total daily dose is within 600 -1200 mg/day.   
RATIONALE: 
To allow more flexibility for the investigator to tailor drug dispensation 
specific to a patient’s needs for maximum benefit of the study medication.  
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SECTION: 
10.1  Study Flow Chart  
REVISION: 
Added the following visits to the current visit schedule: 
• Study Visit 1a for Hematological Monitoring (at Month 2 ±7 days) 
• Study Visit 2a for Hematological Monitoring (at Month 4 ±7 days) 
• Study Visit 3a for Hematological Monitoring (at Month 8 ±7 days) 
• Study Visit 4a for Hematological Monitoring (at Month 10 ±7 days) 
Added the following under each new study visit section 
Patients will return for Study Visit …  At this visit, clinical laboratory 
tests, consisting of the following hematological evaluations (including 
a differential) will be performed: 
• 
Hemoglobin 
• 
Hematocrit  
• 
RBC Count  
• 
WBC Count  
• 
Platelet count 
RATIONALE: 
Added study visits per FDA comment that open label extension trials should 
include more frequent hematological monitoring.   These are now in-line with 
the hematological monitoring frequencies of the double-blind VRX-RET-E22-
302 trial.   
 
 
 
SECTION: 
10.3.  SAFETY ASSESSMENTS 
REVISION: 
[Added] 
Clinical evaluations specific to hematology will be obtained on patients 
on a monthly basis for approximately 4 months and then every two 
months for the next 6 months.  (See Appendix A for Study Flow Chart.) 
 
RATIONALE: 
Added paragraph per FDA comments that the open label extension trial 
should include more frequent hematological monitoring.  These are now in-
line with the hematological monitoring frequencies per the VRX-RET-E22-
302, double-blind trial.   
 
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SECTION: 
10.3.4  LABORATORY ASSESSMENTS, subsection 3  
REVISION: 
IS: 
3.  Pregnancy tests:  
a.   A urine pregnancy test will be performed at Visit 0 to immediately 
confirm non-pregnancy eligibility requirements for female patients of 
child-bearing potential.   
b.  A serum β-HCG pregnancy test for women of childbearing potential 
will be performed at Study Visit 5 and annually thereafter.   
c. A pregnancy test should be performed during the study whenever a 
woman’s menstrual period is 5 days late. 
WAS: 
3. Pregnancy tests: a serum β-HCG pregnancy test for women of 
childbearing potential will be performed at Study Visit 5 and annually 
thereafter.  In addition to the scheduled pregnancy tests, a pregnancy 
test should be performed during the study whenever a woman’s 
menstrual period is 5 days late.   
RATIONALE: 
Reformatted to identify various pregnancy test requirements.  Added urine 
pregnancy test at Visit 0 to provide immediate test results to determine non-
pregnant eligibility of female patients of child-bearing potential.    
 
SECTION: 
10.3.4  LABORATORY ASSESSMENTS  
REVISION: 
Added the following paragraphs 
Laboratory results specific to neutrophil counts will be flagged in the 
laboratory reports if the absolute neutrophil counts are < 1.0 x 103.  For 
all such cases, the investigator shall report these results in an 
expedited manner, whether or not they are considered a serious event. 
Note: For all serious hematological events or infections, the 
investigator shall report these in an expedited fashion, whether 
they are considered unexpected or not.   
 
RATIONALE: 
Added per FDA comments requesting expedited reporting of patients with 
neutrophil counts < 1.0 x 103 and who have serious hematological events or 
infections.  
 
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SECTION: 
10.5  BASELINE 
REVISION: 
Amended to read (see bold text): 
…The final study eligibility…for the open-label extension study [deleted] will 
[added] should be performed at the last visit of the Transition phase...  
[added]  A urine pregnancy test will be performed on female patients of 
child-bearing potential at Visit 0 to immediately confirm the non-
pregnancy eligibility requirements to enter the VRX-RET-E22-304 
study.  After confirmation of [added] all final study eligibility [added] 
requirements… open-label study medication…will be dispensed… 
RATIONALE: 
Added urine pregnancy test at Visit 0 to provide immediate test results to 
determine eligibility of female patients of child-bearing potential.     
SECTION: 
10.20.1  REASON FOR WITHDRAWAL  
REVISION: 
Added bullet point 
• 
Hematological reasons or infections – for all such patients, the 
investigator shall report these in an expedited manner, whether or 
not they are considered serious or unexpected. 
RATIONALE: 
 
Added per FDA comment requesting expedited reporting of all patient 
discontinuations because of hematological reasons or infections.  
SECTION: 
11.1  ASSESSMENT OF EFFICACY 
REVISION: 
(deleted last paragraph) 
Besides the categorical analysis mentioned above, the continuous efficacy 
measurements (such as percent change in monthly total seizure rate from 
the baseline, etc.) will be analyzed by analysis of covariance (ANCOVA) 
with treatment and center as fixed factors and the baseline value of the 
efficacy measurement as covariate. Rank analysis of covariance will be 
used if necessary; however adjusted means will not be presented because 
the data are ranked. The responder rates will be analyzed to check the 
consistency of treatment response in double-blind and open label extension 
studies. The complete details of efficacy analyses will be described in the 
Statistical Analysis Plan. 
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REVISION 
(cont): 
replaced with: 
This is an open-label extension study with the emphasis on safety.  Efficacy 
is not the primary objective of this study unlike the double-blind study VRX-
RET-E22-302.  Descriptive statistics of efficacy measures such as number 
of patients, mean, standard deviation, median, minimum and maximum will 
be provided for continuous variables.  The number and percentages in each 
category will be presented for categorical data.  The pairwise t-test will be 
used to assess whether the retigabine treatment remains effective in the 
open-label extension study if necessary.  The pairwise t-test may be sorted 
by the geographic region [Central/Eastern Europe vs. Rest of World (ROW)]. 
The safety assessments will use essentially the same descriptive statistics 
and pairwise t-test as mentioned above for efficacy.  The complete details of 
efficacy analyses will be described in the Statistical Analysis Plan.  
 
RATIONALE: 
As this is an open-label extension study with the emphasis on safety, as 
opposed to the VRX-RET-E22-302 double-blind study, which emphasizes 
both safety and efficacy, the statistical methods for this open-label extension 
study required revision to address the safety factor appropriately.  
SECTION: 
APPENDIX A.  Study flow chart: 
REVISION: 
Added the following visits to the current visit schedule: 
V 1a - Month 2 
V 2a - Month 4 
V 3a - Month 8 
V 4a - Month 10 
 
Under Study Procedures column, added a new row entitled “Hematological 
Evaluation.”  In this new row, placed an “X” under columns V1a, V2a, V3a 
and V4a     
RATIONALE: 
Added study visits per FDA comment that open label extension trials should 
include more frequent hematological monitoring.  
SECTION: 
APPENDIX A.  Study flow chart: 
REVISION: 
Under Study Procedures column, added a new row entitled “Urine 
Pregnancy Test.”  In this new row, placed an “X” under Visit 0.   
   
RATIONALE: 
Added Urine Pregnancy Test as a new study procedure to be conducted at 
Visit 0 to provide immediate test results to determine non-pregnancy 
eligibility requirements for females of child-bearing potential.     
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4. TABLE OF CONTENTS 
Page 
1. 
Title Page 
2 
2. 
Protocol Sign-Off Sheet 
3 
3. 
SUMMARY OF REVISIONS 
4 
4. 
Table of Contents 
10 
5. 
List of Abbreviations 
13 
6. 
Study Synopsis 
16 
7. 
Introduction 
20 
7.1. 
Background 
20 
7.2. 
Pharmacology 
21 
7.3. 
Preclinical Safety Studies 
22 
7.4. 
Clinical Studies 
23 
7.5. 
Safety and Tolerability 
24 
7.6. 
Pharmacokinetics 
25 
7.6.1. 
Absorption 
25 
7.6.2. 
Metabolism 
25 
7.6.3. 
Excretion 
25 
8. 
Study Objectives 
25 
9. 
Study Design 
26 
9.1. 
Type of Study 
26 
9.2. 
Study Population 
26 
9.3. 
Number of Study Sites 
26 
9.4. 
Treatment Duration 
26 
9.5. 
Patient Inclusion Criteria 
26 
9.6. 
Patient Exclusion Criteria 
27 
9.7. 
Study Medication 
27 
9.7.1. 
Dosage Schedule and Mode of Administration 
28 
9.7.2. 
Study Drug Storage 
28 
9.7.3. 
Study Drug Returns 
29 
9.7.4. 
Method of Assigning Study Medication to Patients 
29 
9.7.5. 
Discontinuation and Tapering of Study Medication 
29 
9.8. 
Assessment of Compliance 
29 
9.9. 
Concomitant Therapy 
30 
9.9.1. 
Permitted Concomitant Medications 
30 
9.9.2. 
Prohibited Medications 
30 
9.10. Protocol Violations and Deviations 
30 
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10. 
Study Procedures 
31 
10.1. Study Flow Chart 
31 
10.2. Efficacy Assessments 
32 
10.3. Safety Assessments 
32 
10.3.1. Vital Sign Measurements and Weight 
32 
10.3.2. Physical and Neurological Examinations 
33 
10.3.3. Electrocardiograms 
33 
10.3.4. Laboratory Assessments 
33 
10.3.5. Post-Void Residual (PVR) Bladder Ultrasound 
35 
10.3.6. AUA Symptom Index 
35 
10.4. Quality of Life Assessments 
36 
10.5. Baseline 
36 
10.6. Study Visit 1 (Month 1) 
36 
10.7. Study Visit 1a (Month 2) 
37 
10.8. Study Visit 2 (Month 3) 
37 
10.9. Study Visit 2a (Month 4) 
38 
10.10. Study Visit 3 (Month 6) 
38 
10.11. Study Visit 3a (Month 8) 
38 
10.12. Study Visit 4 (Month 9) 
39 
10.13. Study Visit 4a (Month 10) 
39 
10.14. Study Visit 5 (Month 12) 
40 
10.15. Study Visits after the First Year 
40 
10.15.1. Visit 6 (Month 16) 
40 
10.15.2. Visit 7 (Month 20) 
41 
10.15.3. Visit 8 (Month 24) 
41 
10.15.4. Visit 9 (Month 28) 
42 
10.15.5. Visit 10 (Month 32) 
42 
10.15.6. Visit 11 (Month 36) 
42 
10.16. Tapering Period 
43 
10.17. Replacement of Patients 
44 
10.18. Unscheduled Visits 
44 
10.19. Laboratory Procedures 
44 
10.20. Early Termination / Withdrawal Visits 
44 
10.20.1. Reasons for Withdrawal 
45 
10.20.2. Handling of Withdrawals 
45 
11. 
Statistical Measurements, Evaluations and Analytical Methods 
46 
11.1. Assessment of Efficacy 
46 
11.2. Assessment of Safety 
47 
11.3. Determination of Sample Size 
47 
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11.4. Additional Statistical Considerations 
48 
11.4.1. Analysis Population 
48 
11.4.2. Handling of Missing Data 
48 
12. 
Adverse Events 
48 
12.1. Definition and Grading Intensity 
49 
12.2. Intensity 
49 
12.3. Criteria for Determining Relationship to Drug 
49 
12.4. Reporting of Adverse Events 
50 
12.4.1. Adverse Events Follow-Up 
50 
13. 
Dose Modifications 
51 
14. 
Monitoring 
51 
15. 
Quality Assurance and Quality Control 
52 
16. 
Drug Accountability 
52 
17. 
Labeling and Packaging of Study Medication 
52 
18. 
Data Handling and Recordkeeping 
53 
18.1. Records 
53 
18.2. Case Report Forms 
53 
19. 
Institutional Review Board 
54 
20. 
Compliance with the Declaration of Helsinki 
54 
21. 
Informed Consent 
54 
22. 
Changes to the Protocol 
55 
23. 
References 
56 
Appendix A. 
Study Flow Chart (REVISED) 
61 
Appendix A. 
Study Flow Chart (ORIGINAL) 
63 
Appendix B. 
Medical Association Declaration of Helsinki 
65 
Appendix C. 
American Urological Association Symptom Index 
71 
Appendix D. 
Protocol Agreement 
72 
 
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5. LIST OF ABBREVIATIONS 
AE 
= 
Adverse event 
AED 
= 
Antiepileptic drug 
ALT 
= 
Alanine aminotransferase 
ANCOVA 
= 
Analysis of covariance 
ANOVA 
= 
Analysis of variance 
APD 
= 
Action potential duration 
AST 
= 
Aspartate aminotransferase 
AUA 
= 
American Urological Association 
AUC 
= 
Area under the curve 
β-HCG 
= 
Beta human chorionic gonadotropin 
BID 
= 
Twice a day 
BMI 
= 
Body mass index 
BP 
= 
Blood pressure 
BUN 
= 
Blood urea nitrogen 
CFR 
= 
Code of Federal Regulations 
CGI 
= 
Clinical global impressions 
CI 
= 
Confidence interval 
Cmax 
= 
Observed maximum plasma concentration 
Cmin 
= 
Observed minimum plasma concentration 
CNS 
= 
Central nervous system 
CPMP 
= 
Committee for Proprietary Medicinal Products 
CRA 
= 
Clinical research associate 
CRF 
= 
Case report form 
CSR 
= 
Clinical study report 
CT 
= 
Computerized tomography 
CV 
= 
Curriculum vitae 
CV% 
= 
Coefficient of variation 
D-20443 
= 
Dihydrochloride salt of retigabine 
ECG 
= 
Electrocardiogram 
EDTA 
= 
Ethylenediaminetetraacetic acid 
EEG 
= 
Electroencephalogram 
EMEA 
= 
European Agency for the Evaluation of Medicinal Products 
FDA 
= 
Food and Drug Administration 
GABA 
= 
Gamma aminobutyric acid  
GCP 
= 
Good Clinical Practice 
hERG 
= 
Human ether-a-go-go related gene 
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HPF 
= 
High power field 
HR 
= 
Heart rate 
ICF 
= 
Informed consent form 
ICH 
= 
International Conference on Harmonization 
IEC 
= 
Independent Ethics Committee 
ILAE 
= 
International League Against Epilepsy 
IND 
= 
Investigational New Drug 
IRB 
= 
Institutional Review Board 
ISE 
= 
Integrated Summary of Efficacy 
ISS 
= 
Integrated Summary of Safety 
ITT 
= 
Intent to treat 
i.v. 
= 
Intravenous 
IVRS 
= 
Interactive Voice Response System 
LFT 
= 
Liver function test 
MAOI 
= 
Monamine oxidase inhibitor 
MedDRA 
= 
Medical Dictionary for Regulatory Activities 
MRI 
= 
Magnetic resonance imaging 
msec 
= 
Milliseconds 
MTD 
= 
Maximum tolerated dose 
N 
= 
Number of patients 
NAT 
= 
N-acetyl transferase 
pH 
= 
Hydrogen Ion Concentration 
PK 
= 
Pharmacokinetics 
PGI 
= 
Patient global impressions 
p.o. 
= 
Oral 
PP 
= 
Per protocol 
PVR 
= 
Post-void residual (bladder ultrasound) 
QD 
= 
Once a day 
QoL 
= 
Quality of Life 
QOLIE-31-P = 
Quality of Life in Epilepsy-Problems Questionnaire 
QTc 
= 
QT correction 
QTcB 
= 
Bazett’s QT correction 
QTcF 
= 
Fridericia’s QT correction 
QTcI 
= 
Individual patient’s QT correction 
RBC 
= 
Red blood cell 
REB 
= 
Research Ethics Board 
SAE 
= 
Serious adverse event 
SAP 
= 
Statistical Analysis Plan 
SD 
= 
Standard deviation 
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SEM 
= 
Standard error of the mean 
SUDEP 
= 
Sudden Unexplained Death in Epilepsy 
t1/2 
= 
Half life 
TdP 
= 
Torsade des Pointes 
TEAE 
= 
Treatment-emergent adverse event 
TID 
= 
Three times a day 
UDPGT 
= 
UDP-glucuronosyltransferase 
UDS 
= 
unscheduled DNA synthesis 
UGT 
= 
uridine diphosphate-glucuronosyltransferase 
ULN 
= 
Upper limit of normal 
URI 
= 
Upper respiratory infection 
UTI 
= 
Urinary tract infection 
Valeant 
= 
Valeant Pharmaceuticals, North America 
VNS 
= 
Vagal nerve stimulator 
WBC 
= 
White blood cell 
WHO 
= 
World Health Organization 
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6. STUDY SYNOPSIS 
TITLE: 
A multicenter, open-label, long-term, safety, tolerability and efficacy 
study of retigabine in adult epilepsy patients with partial-onset 
seizures (Extension of Study VRX-RET-E22-302) 
PHASE: 
3 
OBJECTIVES: 
1. Primary: To evaluate the safety and tolerability of long-term 
therapy with retigabine administered as adjunctive therapy in 
adult epilepsy patients with partial-onset seizures, who 
completed the double-blind Study VRX-RET-E22-302.  
2. Secondary: To evaluate efficacy of long-term treatment with 
retigabine and patient quality of life, evaluated through the 
QOLIE-31-P questionnaire. 
STUDY DESIGN: 
This is an open-label extension study of the placebo-controlled, 
double-blind Study VRX-RET-E22-302.  Patients will be treated with 
600-1200 mg/day of retigabine as an adjunct therapy to their current 
antiepileptic medications (AEDs) or vagal nerve stimulation as 
established in Study VRX-RET-E22-302.  Treatment will be 
continued until retigabine is approved and commercially available, 
or until the program is discontinued, followed by a 3-week tapering 
period and a 30 day post study period for collection of Adverse 
Events (AEs). 
SAMPLE SIZE: 
All patients who complete Study VRX-RET-E22-302 are qualified to 
participate (up to approximately 510 patients). 
NUMBER OF SITES: 
This is a multicenter study involving approximately 55-60 study sites 
in the Western, Central, and Eastern Europe, Australia, Israel, and 
South Africa. 
TREATMENT 
GROUPS: 
All patients will be treated with 600-1200 mg/day of retigabine as an 
adjunct therapy to their current antiepileptic medications (AEDs) or 
vagal nerve stimulation. 
TREATMENT 
DURATION: 
This study will allow the patients who complete Study VRX-RET-
E22-302 to continue with retigabine until the drug is approved and 
commercially available, or until the program is discontinued. 
FORMULATION: 
Retigabine will be supplied by Valeant Pharmaceuticals, Noth 
America in bottles containing tablets in relevant strengths: 50 mg, 
100 mg, or 300 mg. 
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KEY INCLUSION 
CRITERIA: 
1. Patient has successfully completed the Maintenance and 
Transition phases of Study VRX-RET-E22-302 for the treatment 
of partial-onset seizures 
2. Patient is expected to benefit from participation in the study in 
the opinion of the Investigator. 
3. Women of childbearing potential and fertile males have to agree 
to use a medically acceptable method of birth control.  Females 
must have a negative urine pregnancy test at Visit 0, which will 
be confirmed by the serum β-HCG pregnancy test at the last 
visit (Visit 11) of the Transition phase of Study VRX-RET-E22-
302.  A woman of childbearing potential is defined as a female 
who is biologically capable of becoming pregnant.  A medically 
acceptable method of birth control includes an intrauterine 
device in place for at least 3 months, surgical sterilization (e.g. 
tubal ligation), or adequate barrier methods (e.g., diaphragm and 
foam).  An oral contraceptive alone is not considered adequate 
for the purpose of this study. 
4. In the opinion of the Investigator, patient is able to understand 
verbal and written instructions and will adhere to all study 
schedules and requirements. 
5. Patient or legal guardian (if applicable) is informed, given ample 
time and opportunity to read and/or understand about his/her 
participation in the study, and has signed and dated the written 
informed consent form. 
KEY EXCLUSION 
CRITERIA: 
1. Patient meets any of the withdrawal criteria in the previous VRX-
RET-E22-302 study or is experiencing an ongoing serious 
adverse event. 
2. Patient is receiving any investigational drug or using any 
experimental device in addition to Retigabine for treatment of 
epilepsy or any other medical condition. 
3. Patient has any other condition that would prevent compliance 
with the study procedures or proper reporting of AEs. 
4. Female patient who has a positive pregnancy test at any time 
during the study.   
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EVALUATION 
CRITERIA: 
• 
Efficacy: Patients will keep a seizure diary throughout the study. 
The anticonvulsant efficacy of retigabine will be evaluated by 
comparison of baseline seizure frequency (obtained during the 
8-week baseline period of Study VRX-RET-E22-302) with 
seizure frequency obtained during retigabine therapy in this 
study. The primary efficacy variable will be the percentage 
change in the monthly seizure rate from the baseline phase to 
open-label treatment. The proportion of responders (patients 
experiencing ≥ 50% reduction in seizure frequency) from 
baseline to the open-label treatment phase will also be 
evaluated. 
• 
Safety: Safety will be assessed by measurements of vital signs, 
weight, clinical laboratory evaluations (blood chemistry, 
hematology, and urinalysis), 12-lead ECGs, physical and 
neurological examinations, and evaluations of adverse events. 
Patients will additionally be assessed using the American 
Urological Association Symptom Index to assess the urinary 
voiding function. 
 
STATISTICAL 
ANALYSIS: 
The safety population will include all patients who successfully 
complete the Transition phase of Study VRX-RET-E22-302 and 
were included in this long-term study. The Transition phase is the 
phase of Study VRX-RET-E22-302 during which patients were 
adjusted to a 300 mg TID dose of retigabine. No other population for 
analysis is defined for this long-term extension study. 
Assessment of Efficacy: 
"Monthly total partial seizure" as well as "monthly total seizure" rates 
will be calculated for the entire open-label part of Study VRX-RET-
E22-304 and described statistically. 
Baseline monthly total partial seizure rate from Study VRX-RET-
E22-302 will be used for the calculation of difference and % change 
in the open-label study. The % change will be classified into <0, [0, 
25), [25, 50), [50, 75), [75, 100] with a description of the 
frequencies. The responder rate (defined as a reduction in seizure 
frequency ≥50%) is the sum of the upper two classes.   
 
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STATISTICAL 
ANALYSIS 
(cont): 
Assessment of Efficacy (cont): 
The number of seizure free days, in percent to the individual 
duration of the open-label treatment, will be calculated and 
described statistically. In addition, frequencies for this percentage 
will be classified into [0, 25), [25, 50), [50, 75), [75, 95), [95,100), 
=100. The most upper class represents completely seizure free 
patients, the next class almost seizure free patients. 
Additional details will be provided in the Statistical Analysis Plan 
(SAP). 
 
Assessment of Safety: 
All adverse events will be encoded according to MedDRA 8.0. 
Treatment emergent adverse events (TEAE) will be analyzed, i.e. all 
adverse events starting or worsening between the start of the long-
term open-label study up to 30 days after end of taper-off study drug 
at the completion of the open-label study. Incidences on preferred 
term and body system basis will be calculated for all TEAEs. In 
addition, all serious adverse events (SAEs) and all AEs leading to 
premature discontinuation will be presented as separate listings. A 
prospective analysis will be conducted in order to compare the 
results of this study to Study VRX-RET-E22-302. 
TEAE from both studies (double-blind and open-label extension) will 
be combined, i.e. each patient will be counted just once (with 
patient’s respective TEAE). 
Other safety evaluations, such as vital signs, laboratory variables, 
ECG variables, AUA symptom index will be analyzed descriptively. 
Additional details will be provided in the Statistical Analysis Plan 
(SAP). 
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7. INTRODUCTION 
7.1. 
Background 
Epilepsy is among the most common neurological disorders, affecting approximately 50 
million people worldwide.  Classical antiepileptic drugs (AEDs) currently provide 
satisfactory seizure control in approximately 70% of patients; however, the remaining 
30% of epilepsy patients are refractory to treatment.  The partial onset seizure is the 
most common type of seizure that is uncontrolled in adult patients.  The introduction of 
new AEDs (e.g., vigabatrin, lamotrigine, gabapentin, topiramate, levetiracetam, 
oxcarbazepine, zonisamide, and felbamate) during the last decade has increased 
therapeutic possibilities.  However, data from recent clinical trials demonstrate that none 
of the newer AEDs provides adequate seizure control in all patients.  The treatment of 
patients that do not respond to current AEDs remains a problem and motivates the 
continued search for compounds with high antiepileptic potential and low rates of side 
effects.  
Retigabine (GKE-841 or D-23129), N-[2-amino-4(4-fluorobenzylamino)-phenyl] carbamic 
acid ethyl ester, is a new chemical entity discovered by ASTA Medica, Germany, and 
was acquired by Valeant Pharmaceuticals, North America (Valeant) for development as 
an AED for the treatment of partial onset seizures. It is a deaza analog of flupirtine, 
currently marketed in some regions as a centrally acting analgesic with ancillary muscle 
relaxing properties. 
Two Phase 3 studies (VRX-RET-E22-301 and VRX-RET-E22-302) to compare the 
efficacy and safety of Retigabine (600 mg/day, 900 mg/day, or 1200 mg/day) to placebo 
as an adjunctive therapy in refractory patients with partial-onset seizures are currently 
being conducted. These studies are randomized, double-blind, placebo-controlled, multi-
center, parallel-group trials enrolling a total of approximately 790 patients, globally. 
Because of the serious nature of epilepsy, the retigabine clinical program had foreseen 
that all patients who enter and complete a Phase 3 study with retigabine will be given the 
opportunity to continue treatment, if they consent and if the Principal Investigator feels 
they can benefit from continued retigabine treatment. Hence, an open-label extension 
protocol was designed for each double-blind study. 
This study is the open-label extension of the Phase 3 Study VRX-RET-E22-302. VRX-
RET-E22-302 is a randomized, double-blind, placebo-controlled, parallel-group, 
multicenter, study of 900 mg/day and 600 mg/day retigabine versus placebo. During the 
4-week titration phase patients are titrated to the target dose.  510 patients are expected 
to be randomized to treatment. A 12-week maintenance phase follows. All patients who 
wish to enter the open-label extension protocol will enter a 4-week transition phase in 
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which their dose will be titrated to 300 mg TID in order to maintain the blind to the 
maximum extent. Thereafter, the patients could enter this extension study (Study VRX-
RET-E22-304).  Patients who do not wish to enter the open-label extension protocol will 
have their dose tapered over a 3-week period. 
7.2. 
Pharmacology 
Retigabine is a novel antiepileptic compound with a broad spectrum of activity and 
potent anticonvulsant properties.1,2,3,4 Retigabine opens specific potassium channels 
called M channels linked to the KCNQ2/3 and KCNQ3/5 heteromultimeres, which are 
involved in the control of the excitability of neuronal cells.5,6,7,8,9 Mutations in these 
channels were understood to be linked to benign neonatal familial convulsions.10 This 
fact strongly supports the experimental evidence that M-channel activation may be a 
unique and powerful cellular target principle for the treatment of epilepsy. Retigabine 
also has a concentration-dependent ancillary mode of action by increasing gamma 
aminobutyric acid (GABA)-evoked currents.  These effects, however, were seen at 
concentrations of 10 μmol/L, whereas the potassium channel-opening effects occur at 
concentrations as low as 0.1 μmol/L.11,12 
Results from preclinical studies revealed that retigabine is effective in a broad range of 
animal models of epileptic seizures. Amygdala kindling is considered the most predictive 
animal model for human complex partial seizures.13 In kindled rats, intraperitoneal or oral 
doses of retigabine as low as 0.01 mg/kg were effective in increasing the threshold for 
induction.14 At a higher dose of 5 mg/kg retigabine also reduced seizure severity, seizure 
duration, and post-discharge duration in fully kindled rats.14 A clear separation between 
antiepileptic and neurotoxic effects is evident in these preclinical models.  In addition, 
preclinical testing has not revealed any tolerance, dependence, or withdrawal liabilities 
for retigabine.15 
Retigabine is rapidly absorbed following p.o. (oral) administration with peak plasma 
concentrations being achieved 1-2 hours after dosing in mice and rats.16,17 The absolute 
bioavailability ranged from 44% to 70%.17 Retigabine is extensively distributed and 
rapidly eliminated from all tissues in rats over a 48- to 72-hour period after dosing.18,19 
Retigabine is primarily metabolized by acetylation, glucuronidation, and oxidation 
mechanisms in rats and by glucuronidation in dogs. The active N-acetyl metabolite of 
retigabine has a pharmacological profile similar to retigabine but is 20 times less 
potent.20 The major route of excretion in rats and dogs is in feces, with some compound 
being excreted in urine.21,22,23 In humans, retigabine is mainly metabolized by N-
glucuronidation and N-acetylation, and is not metabolized by cytochrome P450 
enzymes.20 Retigabine has low protein binding in all species, including humans.20 Both in 
vivo and in vitro studies suggest that retigabine is unlikely to have any important drug-
drug interactions with commonly used drugs.24,25,26,27 
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7.3. 
Preclinical Safety Studies 
Retigabine caused motor impairment in rodents in the rotarod test, but the doses 
necessary were 12 to 13 times higher than those active in models of epilepsy.28 Neither 
retigabine nor its N-acetyl metabolite prolonged action potential duration (APD) in cat 
cardiac myocytes and dog Purkinje fibers, and in fact resulted in slight shortening of 
APD in these test systems.29  At concentrations 17-20 times higher than those achieved 
at therapeutic doses in man, retigabine caused a slight prolongation in QT interval in the 
isolated guinea pig heart, as well as a slight reduction in K+ current through human 
ether-a-go-go related gene (hERG) channels.30 However, retigabine did not affect ECG 
parameters in anesthetized dogs or conscious unrestrained dogs given daily doses for 7 
days.31 Retigabine may inhibit bladder contractions and micturition in rodents due to its 
ability to hyperpolarize and stabilize urinary bladder myocytes through activation of K+ 
channels.32 
In acute and chronic toxicity studies in rats, CNS related clinical signs including 
hyperkinesia, hypokinesia, disturbed coordination, stilted gait, tremor and convulsions 
were observed.33 In repeat dose toxicity studies in rodents, slight hepatocellular and 
thyroid follicular hypertrophy were observed and were considered to be adaptive.34,35 In 
repeat-dose studies in dogs but not rodents, self-limiting hepatocellular degeneration 
was observed in regions adjacent to the gallbladder.36,37 In rodents but not dogs, 
distended urinary bladder or urinary bladder ectasia was noted with occasional 
secondary inflammation and ulceration of bladder wall.34,35,36,37 
No retigabine-related effects on reproductive function were observed in male or female 
rats in a fertility and general reproductive performance study.  No teratogenic effects of 
retigabine were observed in rats or rabbits.38,39 In a perinatal and postnatal toxicity study 
in rats, the administration of retigabine to mated females did not have significant effect 
on the development of the offspring, but at the highest dose level growth was slowed, 
early mortality increased, and auditory reflex development was retarded in relation to the 
delay in growth.40  In juvenile rats, retigabine reduced food consumption at the maximum 
tolerated dose but did not affect growth, reflex development, motor activity, learning, 
memory, clinical pathology parameters, or reproductive performance.41  
In genetic toxicity studies, the retigabine active substance, used to manufacture finished 
product, tested negative for mutagenicity in the AMES test.  Some exceptions could be 
explained as false weakly positive results due to alterations of the Salmonella tester 
strains.42,43 Retigabine was negative in 2 independent mammalian cell forward gene 
mutation assays in presence and absence of S-9.42  Retigabine did not induce 
chromosome aberrations in cultured human lymphocytes following pulse treatment for 3 
or 4 hours in the absence and presence of S-9.43  Following continued treatment for 20 
or 22 hours in this test system, retigabine induced chromosome aberrations, but only in 
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the absence of S-9.  Retigabine tested negative in genetic toxicity studies relying for 
metabolism on unbroken cells where the required cofactors are present at their natural 
concentrations as in the in vivo micronucleus test in mice and in the in vivo / in vitro 
unscheduled DNA synthesis (UDS) assay in hepatocytes in rats.44, 45, 46, 47, 48 
7.4. 
Clinical Studies 
In open-label Phase 2 studies in patients with epilepsy, the majority of patients tolerated 
daily doses of up to 1200 mg administered orally in two or three divided doses.  The 
most commonly observed treatment-emergent adverse effects were in the MedDRA 
system organ class of Nervous System Disorders.  In a double-blind parallel group study 
comparing different titration rates (Study 3065A1-214), it has been shown that when the 
starting dose of retigabine is 300 mg/day (100 mg TID), the daily dose can be titrated to 
1200 mg over a 6-week period with only 13% of patients discontinuing due to adverse 
events.  
In a randomized, double-blind, placebo-controlled, parallel group study comprising 
397 patients with epilepsy (Study 3065A1-205)52, daily doses of 900 mg and 1200 mg 
(administered orally in three divided doses) caused a significant reduction in total partial 
seizure frequency compared with placebo.  While a dose of 600 mg/day resulted in 
greater reduction of seizure frequency than placebo, the difference was not statistically 
significant.  The majority of patients tolerated their treatment as prescribed, with a 
minority discontinuing from the study prematurely. The discontinuation rate due to 
adverse events in 1200 mg dose group was about 2.5 times that in placebo group.  This 
is consistent with tolerability of other AEDs.  The commonly observed adverse events 
were in the MedDRA system organ class of Nervous System Disorder and many of 
these were dose related and were more frequent with retigabine compared with placebo.  
There were few clinically important changes in vital signs, laboratory, or ECG 
parameters, or physical or neurological examinations. 
Patients participating in Study 3065A1-205 were eligible for an open-label extension 
phase (Study 3065A1-212) if they experienced improvement in seizure control, did not 
experience adverse events that would prevent inclusion, and did not violate the double-
blind study protocol.  Patients who completed the interim (transition) phase of the 
double-blind portion of the study started with 300 mg TID, which could be increased 
weekly in increments of 150 mg/day, up to a maximum of 1200 mg daily.  Concomitant 
AEDs could be adjusted to achieve the best efficacy/safety ratio.  Patients who wished to 
discontinue retigabine during this open-label study entered a 3-week tapering period and 
a 10-day post-study follow-up period.  Seizure frequency was recorded daily in a diary 
maintained by each patient.  The efficacy of retigabine was evaluated by comparison of 
baseline seizure frequency (determined upon entry into the double-blind phase) with 
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seizure frequency during retigabine therapy in the extension study; this was calculated 
as a percentage change in total partial seizure frequency. 
Of the 279 patients who completed Study 205, 222 enrolled in the open-label extension.  
The majority of these patients were white (213 or 95.9%) with a median age of 36 years.  
A total of 126 patients were male (56.8%) and 96 (43.2%) were female. The median 
duration of epilepsy at study entry was 20.7 years.  Of these 222 patients, 18 (8%) 
discontinued within the first 3 months and 41 (18%) discontinued within 6 months. The 
most common cause for discontinuation was lack of efficacy.  The most common daily 
dosage of retigabine was 900 mg (105 patients; 47.3%) and only a minority of the 
patients titrated the dosage to 1200 mg (53 patients; 23.9%).  The median treatment 
duration during open-label extension phase was 358 days. 
The median decrease in monthly total partial seizure frequency from baseline was 
48.3%, which was similar to the results with the two highest retigabine dose groups 
(300 and 400 mg TID) in the randomized, double-blind phase.  Patients assigned to the 
placebo group during the double-blind phase showed the largest seizure rate 
improvement during the extension phase. One hundred three patients (46.4%) showed a 
reduction in monthly total partial seizure frequency of 50%. 
7.5. 
Safety and Tolerability  
The safety and tolerability of various dosing regimens of retigabine were examined in 
healthy patients participating in human pharmacology studies and in patients with 
epilepsy in therapeutic trials.53,54 A total of 404 healthy subjects participated in 18 human 
pharmacology studies.  In a multiple dose-finding trial using fixed doses, regimens up to 
200 mg twice a day (BID) were safe and well tolerated and the maximum tolerated dose 
was found to be 250 mg BID.  However, after allowing for titration to the target dose, 
regimens up to 350 mg BID were tolerated without any dose-limiting adverse events 
(AEs). In general, central nervous system (CNS) AEs limited further dose increases.55 
A total of 605 patients with epilepsy have been enrolled in clinical studies for retigabine. 
Retigabine was mostly administered as add-on therapy to various established 
background AEDs and to a minor extent as monotherapy by using various dose-titration 
regimens.  The maximum tolerated dose (MTD) of retigabine when added to standard 
AEDs was 1200 mg/day.  Retigabine was administered using BID and TID regimens. 
The most common AEs were CNS-related (e.g., somnolence, dizziness, confusion, 
speech disorder, vertigo, amnesia, thinking abnormal, tremor, incoordination, ataxia, 
nervousness, paresthesia, abnormal gait, diplopia, and abnormal vision) and appeared 
in a dose-dependent manner.55  No AEs of retigabine on cardiac safety and in particular 
cardiac repolarization (QTc interval) were detected.  While the AE pattern from human 
pharmacology and clinical trials is similar, it is interesting to note that MTDs in healthy 
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subjects appear to be different from those achieved in patients with epilepsy, despite the 
concomitant medication with standard AEDs in the latter group.  
A complete description of preclinical pharmacology, toxicology, PK studies, and clinical 
safety and efficacy studies for retigabine can be found in the Investigator’s Brochure.56 
7.6. 
Pharmacokinetics 
7.6.1. 
Absorption  
In clinical trials, retigabine was rapidly absorbed within 2 hours after oral administration 
to healthy patients.49 The N-acetylated metabolite of retigabine was also rapidly formed, 
following the parent compound by approximately 2 hours.  Both retigabine and the N-
acetylated metabolite of retigabine were eliminated with a half-life (t1/2) of about 8 hours.  
At steady state, mean observed maximum concentration (Cmax) and area under the 
curve (AUC) values of the N-acetylated metabolite were within 20% of the corresponding 
mean values of retigabine.  The trough plasma concentrations of retigabine in the 
afternoon or evening were significantly lower than those in the morning, possibly related 
to slower metabolism during sleep.  The pharmacokinetics (PK) of retigabine and the N-
acetylated metabolite of retigabine were linearly dose proportional for doses from 100 to 
350 mg.  
7.6.2. 
Metabolism 
Investigations of metabolism in humans indicate that retigabine is mainly metabolized by 
N-glucuronidation and N-acetylation, and is not metabolized by cytochrome P450 
enzymes.20 In vitro studies have shown that the glucuronidation is performed by several 
uridine diphosphate glucuronyltransferase (UGT) isozymes.50 The PK of retigabine and 
the N-acetylated metabolite of retigabine in patients with epilepsy are comparable with 
those in healthy subjects.51 
7.6.3. 
Excretion 
The major route of excretion in rats and dogs is in feces, with some compound being 
excreted in urine.21,22,23 In humans, retigabine is mainly metabolized by N-
glucuronidation and N-acetylation, and is not metabolized by cytochrome P450 
enzymes.20 Retigabine has low protein binding in all species, including humans.20 Both in 
vivo and in vitro studies suggest that retigabine is unlikely to have any important drug-
drug interactions with commonly used drugs.24,25,26,27 
8. STUDY OBJECTIVES 
• 
Primary: To evaluate the safety and tolerability of long-term therapy with 
retigabine administered as adjunctive therapy in adult epilepsy patients with 
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partial-onset seizures, who completed the double-blind Study VRX-RET-E22-
302. 
• 
Secondary: To evaluate efficacy of long-term treatment with retigabine and 
patient quality of life, evaluated through the QOLIE-31-P questionnaire. 
9. STUDY DESIGN 
This is an open-label extension study of the placebo controlled, double-blind Study VRX-
RET-E22-302. Patients will be treated with 600-1200 mg/day of retigabine as an adjunct 
therapy to their current antiepileptic medications (AEDs) or vagal nerve stimulation as 
established in Study VRX-RET-E22-302. Following completion of the Transition Phase 
of the double-blind study (Study VRX-RET-E22-302), treatment in this open-label 
extension study will be continued until retigabine is approved and commercially 
available, or until the program is discontinued, followed by a 3-week tapering period and 
a 30 day post-study period for collection of adverse events. 
9.1. 
Type of Study 
Phase 3 open-label extension study for therapeutic use. 
9.2. 
Study Population 
Patients entering this study had to have participated in Study VRX-RET-E22-302, i.e. 
they had met eligibility criteria of that study and completed the double-blind phase. 
9.3. 
Number of Study Sites 
This is a multi-center open-label study involving approximately 55-60 study sites in 
Western, Central and Eastern Europe, Australia, Israel, and South Africa. 
9.4. 
Treatment Duration 
Following completion of the Transition Phase of the double-blind study (Study VRX-RET-
E22-302), treatment in this open-label extension study will be continued until retigabine 
is approved and commercially available, or until the program is discontinued, followed by 
a 3-week tapering period and a 30 day post-study period for collection of adverse 
events.   
9.5. 
Patient Inclusion Criteria 
For inclusion in the study, a patient must meet and comply with the following criteria: 
1. Patient has successfully completed the Maintenance and Transition phases of Study 
VRX-RET-E22-302 for the treatment of partial-onset seizures 
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2. Patient is expected to benefit from participation in the study in the opinion of the 
Investigator. 
3. Women of childbearing potential and fertile males have to agree to use a medically 
acceptable method of birth control and females shall have a negative urine 
pregnancy test at Visit 0, which will be confirmed by the serum β-HCG pregnancy 
test at the last visit (Visit 11) of the Transition phase of Study VRX-RET-E22-302.   A 
woman of childbearing potential is defined as a female who is biologically capable of 
becoming pregnant.  A medically acceptable method of birth control includes an 
intrauterine device in place for at least 3 months, surgical sterilization (e.g. tubal 
ligation), or adequate barrier methods (e.g., diaphragm and foam).  An oral 
contraceptive alone is not considered adequate for the purpose of this study. 
4. In the opinion of the Investigator, patient is able to understand verbal and written 
instructions and will adhere to all study schedules and requirements. 
5. Patient or legal guardian (if applicable) is informed, given ample time and opportunity 
to read and/or understand about his/her participation in the study, and has signed 
and dated the written informed consent form. 
9.6. 
Patient Exclusion Criteria 
A patient is ineligible for entering Study VRX-RET-E22-304 if any of the following 
exclusion criteria are met: 
1. Patient meets any of the withdrawal criteria in the previous VRX-RET-E22-302 study 
or is experiencing an ongoing serious adverse event. 
2. Patient is receiving any investigational drug or using any experimental device in 
addition to Retigabine for treatment of epilepsy or any other medical condition. 
3. Patient has any other condition that would prevent compliance with the study 
procedures or proper reporting of AEs. 
4. Female patient who has a positive pregnancy test at any time during the study. 
 
9.7. 
Study Medication 
Study medication will be supplied by Valeant Pharmaceuticals, North America, as film-
coated tablets containing 50 mg, 100 mg, or 300 mg of retigabine per tablet. Tablets will 
be packaged in induction sealed bottles.  A sufficient supply of study medication will be 
provided to each site for completion of the trial, based on the number of patients 
enrolled, study visit schedule, and the daily doses of patients. Specific dosage 
instructions will be provided separately to the patient. All study medication will be 
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dispensed by the pharmacy or an appropriately qualified member of the study staff 
assigned by the Principal Investigator to this task. 
Patients will take the established background AEDs from their own prescriptions, and 
their use will be recorded. 
9.7.1. 
Dosage Schedule and Mode of Administration 
Patients who completed the Transition phase of Study VRX-RET-E22-302 will start with 
300 mg three times a day (300 mg TID).  Patients who were not able to tolerate the final 
dose adjustment (750 mg/day) during the last week of the Transition phase of Study 
VRX-RET-E22-302 will start with 200 mg three times a day (200 mg TID).   
If, in the opinion of the Investigator, the patient was not receiving the maximum effective 
dose, the dose could be increased in weekly intervals of 150 mg/day, up to a maximum 
of 1200 mg daily (i.e. 400 mg TID). If adverse events considered to be secondary to 
retigabine occur, the total daily dose could be reduced by 150 mg/day every week, at 
Investigator discretion, as long as the dose is within 600-1200 mg/day. 
At the investigator’s discretion, patients may also start with another dose regimen that 
can be either BID or TID, and is not required to be equally distributed throughout the day 
(e.g., if a patient experiences somnolence and the investigator decides to dose the 
patient higher in the evening) as long as the total daily dose is within 600 -1200 mg/day. 
After the patient has entered open-label treatment, the Investigator may add new AEDs, 
as long as these are approved AEDs. In addition, the existing background AED therapy 
can be adjusted to achieve the best efficacy/safety ratio, as needed, per Investigator 
discretion. If necessary, in the Investigator’s judgment, all background AEDs can be 
discontinued to achieve monotherapy with retigabine. 
Patients who permanently discontinue open-label treatment will have their dose tapered 
by one-third every week. 
Patients will be instructed on the administration procedures for study drug. Study 
medication will be administered orally with or without food. The 3 daily doses are to be 
administered with approximately an 8-hour interval between them (for example 7am, 
3pm, 11pm). Patients will continue to take their established background AEDs from their 
own prescriptions. 
9.7.2. 
Study Drug Storage 
All study drug sent to the study centers must be stored under the conditions specified on 
the drug package label (15 – 30 °C / 59 – 86 °F) in a secure area accessible only to the 
Investigator and his/her designated staff.  All study drugs should be stored and 
inventoried according to applicable government regulations and study procedures. 
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9.7.3. 
Study Drug Returns 
Government regulations require that all investigational drug materials not used in clinical 
trials be returned before or at the completion of the study. 
The Investigator will return the designated copies of the completed dispensing and 
inventory record. 
9.7.4. 
Method of Assigning Study Medication to Patients 
Study medication will be assigned to patients through a centralized Interactive Voice 
Response System (IVRS), as described in the IVRS user manual that will be provided to 
the sites.  Sites will contact the IVRS to obtain the package number assignment(s) for 
patients at each scheduled study visit 
Study personnel will select the study medication bottle(s) from their inventory that 
correspond to the package number(s) assigned by IVRS. Study personnel will complete 
the tear-off labels on the bottles, affix them to the Investigational Product Labels page 
found in the patient’s paper source binder, and dispense the study medication (bottles) 
to the patient.  At subsequent study visits, study personnel will follow the same 
procedures as described above, contacting the IVRS as instructed in the IVRS manual. 
9.7.5. 
Discontinuation and Tapering of Study Medication 
Patients who discontinue early from the open-label extension study will have their study 
medication tapered over a 3-week period, reducing their daily dose by one-third per 
week. After tapering has been completed, patients should return to the site immediately, 
and complete all assessments and evaluations scheduled for Visit 5, if patient 
discontinued early during the first year of the open-label extension study, complete all 
assessments and evaluations scheduled for Visit 8 if patient discontinued early during 
the second year of the open-label extension study, and complete all assessments and 
evaluations scheduled for Visit 11 if patient discontinued early during the third year of the 
open-label extension study (Refer to Study Flow Chart in Appendix A). 
9.8. 
Assessment of Compliance 
Patient compliance with the study drug dosing regimen will be assessed by counts of 
tablets remaining in the study medication bottles that are returned at each study visit.  
Compliance will be based on the medication the patient was scheduled to take for the 
days between study visits.  In addition, information on the average total daily dose will be 
calculated, based on the number of tablets remaining or returned in each bottle. 
Patients will be instructed to bring used and unused study medication bottles with them 
to each study visit for accountability purposes. Tablets from each bottle for each dose 
strength (50 mg, 100 mg, 300 mg) will be counted and recorded to assess patient 
compliance and correct dosage taken.  If a patient is deemed to be non-compliant with 
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taking study medication, the patient should be counseled by the site.  If the patient 
continues to be non-compliant, they should be withdrawn from the study. 
Along with drug accountability logs, the CRF will capture the data which includes the 
prescribed dosage, dates of first dose and last dose, and the number of tablets returned 
from each bottle for each dose strength. The CRFs will also provide a classification in to 
poly- or monotherapy with retigabine. 
9.9. 
Concomitant Therapy 
9.9.1. 
Permitted Concomitant Medications 
Patients will take the background AED as prescribed by their physician. If adverse 
events considered to be secondary to retigabine occur, the total daily dose could be 
reduced by 150 mg/day every week, at Investigator discretion, as long as the dose is 
within 600-1200 mg/day.  The background AED therapy can be adjusted if a patient 
develops adverse events similar to the previously experienced reaction to that AED.   
After patients enter the open-label extension study, the Investigator will be allowed to 
adjust background AEDs, as clinically indicated.  As needed, the background AED 
therapy can be adjusted to achieve the best efficacy/safety ratio, per Investigator 
discretion.  If necessary, in the Investigator judgment, all background AEDs can be 
discontinued to achieve monotherapy with retigabine.  The dose and reason to use a 
concomitant medication shall be recorded in the CRFs. 
9.9.2. 
Prohibited Medications 
Use of felbamate and vigabatrin are prohibited. Concurrent use of any AEDs, or of any 
drug that could interfere with the absorption or metabolism of retigabine and background 
AED is also prohibited.  Medications known to lower seizures (e.g. neuroleptics) and 
monoamine oxidase inhibitors (MAOIs) are not allowed. 
9.10. Protocol Violations and Deviations 
A deviation from the protocol is an unintended and/or unanticipated departure from the 
procedures and/or processes approved by the Sponsor and the IRB/IEC/REB and 
agreed to by the Investigator. Deviations usually have an impact on individual patients or 
a small group of patients. A protocol violation occurs when there is non-adherence to the 
protocol that results in a significant, additional risk to the patient, when the patient or 
Investigator has failed to adhere to critical protocol requirements (inclusion/exclusion 
criteria) and the patient was enrolled without prior Sponsor approval, or when there is 
non-adherence to FDA regulations and/or ICH GCP guidelines. 
The Investigator or designee must document and explain any deviation or violation from 
the approved protocol. The Investigator may implement a deviation from, or a change of 
the protocol to eliminate an immediate hazard to study patients without prior 
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IRB/IEC/REB approval. Immediately after the implemented deviation, violation or change 
to eliminate the immediate hazard to the study patient(s), the Investigator must submit a 
report explaining the reasons for the protocol deviation, violation or change to the 
Sponsor. If required, the regulatory authorities will be notified. The appropriate 
IRB/IEC/REB will be notified of specified, critical violations or violations that place 
patients at added, significant risk. 
Protocol violations and deviations will be documented by the clinical monitor throughout 
the course of the monitoring visits. Investigators will be notified of violations and 
deviations and/or in writing by the monitor, and the Principal Investigator will be required 
to identify corrective action to eliminate future violations and deviations. 
10. STUDY PROCEDURES 
10.1. Study Flow Chart 
As presented in the Study Flow Chart (see Appendix A), Study Visit 1 will have a window 
range of ±3 days.  After Study Visit 1, all remaining study visits will have a window range 
of ±7 days around that visit day to accommodate individual schedules, as follows: 
• 
Baseline for the open-label extension study corresponds to the assessments 
performed at the last visit of the Maintenance phase (Visit 9) of Study VRX-RET-E22-
302 for all patients.  The final, baseline eligibility assessment for the open-label 
extension study, including obtaining informed consent and dispensing open-label study 
medication will be performed at the last visit of the Transition phase (Visit 11) of Study 
VRX-RET-E22-302. 
• 
Study Visit 1 (at Month 1 ±3 days) 
• 
Study Visit 1a for Hematological Monitoring (at Month 2 ±7 days) 
• 
Study Visit 2 (at Month 3 ±7 days) 
• 
Study Visit 2a for Hematological Monitoring (at Month 4 ±7 days) 
• 
Study Visit 3 (at Month 6 ±7 days) 
• 
Study Visit 3a for Hematological Monitoring (at Month 8 ±7 days) 
• 
Study Visit 4 (at Month 9 ±7 days) 
• 
Study Visit 4a for Hematological Monitoring (at Month 10 ±7 days) 
• 
Study Visit 5 (at Month 12 ±7 days). 
• 
Study Visit 6 (at Month 16 ±7 days) 
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• 
Study Visit 7 (at Month 20 ±7 days). 
• 
Study Visit 8 (at Month 24 ±7 days). 
• 
Study Visit 9 (at Month 28 ±7 days). 
• 
Study Visit 10 (at Month 32 ±7 days). 
• 
Study Visit 11 (at Month 36 ±7 days). 
Each study month will be defined as 30 calendar days.  If a patient visit occurs outside 
the visit window, the study clinical monitor (CRA) should be notified and the reason for 
the deviation noted. An attempt should be made to ensure that the patient returns for 
subsequent visits on schedule using the last visit of the Transition phase (Visit 11) of 
Study VRX-RET-E22-302, which corresponds to the final, baseline eligibility visit for the 
open-label extension study. 
10.2. Efficacy Assessments 
Patients will keep a seizure diary throughout the study. The anticonvulsant efficacy of 
retigabine will be evaluated by comparison of baseline seizure frequency (obtained 
during the 8-week baseline period of Study VRX-RET-E22-302) with seizure frequency 
obtained during retigabine therapy in this open-label extension study (VRX-RET-E22-
304). The primary efficacy variable is the percentage change in the monthly seizure rate 
from the baseline phase to the open-label treatment phase. The proportion of 
responders (patients experiencing ≥ 50% reduction in seizure frequency) from baseline 
to the open-label treatment phase will also be evaluated. 
10.3. Safety Assessments 
Safety assessments will be evaluated, based on reports of AEs and results of vital signs 
(supine and standing blood pressure, pulse, and temperature), weight, clinical laboratory 
evaluations (blood chemistries, hematology and urinalysis including microscopy), a 12-
lead ECG, and physical and neurological examinations. Post-void residual (PVR) 
bladder ultrasounds to assess urinary retention and the American Urological Association 
(AUA) Symptom Index to assess urinary voiding function will also be performed during 
the first year of the open-label extension study. 
Clinical evaluations specific to hematology will be obtained on patients on a monthly 
basis for approximately 4 months and then every two months for the next 6 months.  
(See Appendix A for Study Flow Chart.) 
10.3.1. 
Vital Sign Measurements and Weight 
Complete vital sign measurements (including supine and standing blood pressure, heart 
rate, and temperature) will be obtained throughout the study at all visits. Evaluations of 
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blood pressure and heart rate will be performed supine at each study visit, and again 
after the patient has been standing for approximately 2 minutes.  
Weight [pounds (lb) or kilograms (kg)] will also be measured in ordinary indoor clothing 
(without shoes) and will be recorded at all study visits  
Abnormal vital sign values that are deemed clinically significant by the Investigator will 
be reported as AEs in the study CRF. 
10.3.2. 
Physical and Neurological Examinations 
A complete physical and neurological examination will be performed annually at Visit 5, 
Visit 8, and Visit 11.  Brief neurological examinations will be performed at all other study 
visits, including visits 1, 2, 3, 4, 6, 7, 9, and 10. 
10.3.3. 
Electrocardiograms 
A 12-lead ECG will be performed at all study visits during the first year of the open-label 
extension study (Visits 1, 2, 3, 4, 5), and annually at Visits 8 and 11. The ECG 
parameters that will be assessed are heart rate, PR interval, QRS interval, QT interval, 
and QTc interval.  All ECG tracings will be sent to Quintiles ECG Services for central 
reading.  Quintiles ECG Services will provide a central ECG analysis and transmit a 
feedback of preliminary results via facsimile to the investigation site within 24 hours.  
Trained technicians will read all ECGs manually, and any abnormal finding will then be 
over-read by board-certified cardiologists.  QT intervals will be corrected using both 
Bazett’s and Fridericia’s formulas.  For purposes of clinical study conduct, Bazett’s QT 
correction will be used.  For purposes of data analysis, Fridericia’s QT correction will be 
considered as primary.  Changes from baseline QTc interval will be monitored on an 
ongoing basis throughout this study.   
Increases in Bazett’s QTc interval of >60 msec from baseline or QTc interval of >500 
msec anytime during the study should be confirmed on a repeat ECG.  Any such 
occurrence shall result in notification of the Investigator and the study medical monitor 
for immediate review of the tracings and discussion with Valeant. 
10.3.4. 
Laboratory Assessments 
All clinical laboratory assessments will be performed by a central laboratory (Quintiles 
Central Laboratory Services), which will provide instructions and supplies to the study 
staff before study initiation.  Results of the clinical laboratory assessments will be faxed 
back to the study site within 48 to 72 hours of sampling.  Alert values will be reported to 
the Investigator via telephone.  Approximately 7-mL sample of blood will be drawn for 
clinical chemistries and hematology assays.  The laboratory assessments will include 
routine laboratory tests.  The clinical laboratory evaluation will be performed at all study 
visits during the open-label extension study. 
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Because of the bladder toxicity observed in chronic toxicology studies in the rat and 
mouse, careful attention will be paid to plasma creatinine and blood urea nitrogen 
(BUN), microscopic findings on urinalysis, and any symptoms that might suggest 
incomplete bladder emptying (e.g., urinary tract infection, frequency, sensation of 
incomplete voiding, etc.).  All patients will undergo urinalysis (including microscopy) at all 
study visits. 
Any patient who has developed a clinically significant urinalysis abnormality will undergo 
further evaluation by an urologist (as clinically indicated) for any of the following: 
• 
>5 red blood cells (RBC) per high power field (HPF) for males and 
postmenopausal females or >8 RBC/HPF for females 
• 
>3 white blood cells(WBC) per high power field (HFP) for males and >12 
WBC/HPF for females 
• 
>1+ epithelial cells 
• 
≥1+ on all casts except Hyaline casts ≥2+ 
• 
>1+ blood for males and postmenopausal females 
• 
≥1+ trace protein [RBC; males and postmenopausal females] per high power 
field (HPF) or >5 white blood cells [WBC; must have 1 to few epithelial cells/HPF] 
per HPF, >occasional casts, >1+ blood [male and postmenopausal female 
patients] or >trace protein 
• 
Have symptoms or AEs suggestive of possible hypotonicity of the bladder 
The laboratory evaluations will include: 
1. Hematology: hemoglobin, hematocrit, RBC count, WBC count with differential, and 
platelet count. 
2. Blood chemistries: sodium, potassium, chloride, bicarbonate, glucose, cholesterol, 
creatinine, calcium, phosphorus, BUN, uric acid, total bilirubin, total protein, AST, 
ALT, and alkaline phosphatase levels.  
3. Pregnancy tests:  
a.   A urine pregnancy test will be performed at Visit 0 to immediately confirm non-
pregnancy eligibility for female patients of child-bearing potential.   
b.  A serum β-HCG pregnancy test for women of childbearing potential will be 
performed at Study Visit 5 and annually thereafter.   
c. A pregnancy test should be performed during the study whenever a woman’s 
menstrual period is 5 days late. 
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4. Routine urinalysis: specific gravity, pH, protein/albumin, glucose/sugar, 
ketones/acetone, and hemoglobin/blood.  In order to standardize measurements, 
Bayer multistix 8-SG or equivalent dipsticks will be used.  
5. Microscopic urinalysis: RBC, WBC, casts, and crystals/cells. 
All laboratory tests with values that become abnormal after drug administration will be 
repeated as clinically indicated until the values return to normal, or until the etiology has 
been determined and the condition considered stable. Abnormal laboratory test results 
that are considered to be clinically important by the Investigator will be reported as an 
AE in the CRF.  A laboratory abnormality will not be considered an AE unless: 
• 
Intervention is required. 
• 
Changes in dose of retigabine are required (decrease, discontinued, interrupted). 
• 
Other treatment/therapy is required. 
• 
Associated with other diagnoses 
Laboratory results will be reported to the Investigator who will review abnormal 
laboratory findings for clinical significance.  The Investigator will note any laboratory test 
results of clinical concern, or values that were outside normal ranges and provide details 
of the relationship to study drug and the action taken.  If a change in a laboratory value 
represents a medical condition, the medical condition will be listed in the AE record. If no 
correlation is possible, the direction of change (increase or decrease) rather than the 
actual value will be recorded. 
Laboratory results specific to neutrophil counts will be flagged in the laboratory reports if 
the absolute neutrophil counts are < 1.0 x 103.  For all such cases, the investigator shall 
report these results in an expedited manner, whether or not they are considered a 
serious event. 
Note: For all serious hematological events or infections, the investigator shall report 
these in an expedited fashion, whether they are considered unexpected or not. 
10.3.5. 
Post-Void Residual (PVR) Bladder Ultrasound 
A post-void residual (PVR) bladder ultrasound to assess urinary retention will be 
performed at Visits 1, 2, and 5, during the first year of the open-label extension study. 
10.3.6. 
AUA Symptom Index 
An AUA Symptom Index, a 7-item Likert-scored scale describing urinary bladder 
function, will be completed by the Investigator at Visits 1, 2, and 5, during the first year of 
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the open-label extension study, to assess the patient’s urinary voiding function. The AUA 
Symptom Index is included in Appendix D of this protocol. 
10.4. Quality of Life Assessments 
The QOLIE-31-P (Version 2.0) will be utilized to assess quality of life. The QOLIE-31-P 
assessment must be completed by the patients.  Patients who are cognitively impaired 
and cannot complete the QOLIE-31-P assessment may still participate in the study, by 
obtaining a waiver for QOLIE-31-P completion from the study medical monitor. 
10.5. Baseline 
Except for final study eligibility, informed consent and dispensation of open-label 
extension study medication, the Baseline assessments for the open-label extension 
study correspond to the assessments performed at the last visit of the Maintenance 
phase (Visit 9) of Study VRX-RET-E22-302 (See Study Flow Diagram - Appendix A).  
After completion of all study procedures on the last visit of the Transition phase (Visit 11) 
of Study VRX-RET-E22-302, patients will be allowed to enter this open-label extension 
study (VRX-RET-E22-304).  All ongoing AEs and concomitant medications at the last 
visit of the Transition Phase (Visit 11) of Study VRX-RET-E22-302 will need to be 
transferred and captured on the appropriate open-label extension AE and Concomitant 
Medication CRF pages.  The final study eligibility and informed consent for the open-
label extension study should be performed at the last visit of the Transition phase (Visit 
11) of Study VRX-RET-E22-302.  A urine pregnancy test will be performed on female 
patients of child-bearing potential, to immediately confirm the non-pregnancy eligibility 
requirements tp enter the VRX-RET-E22-304 study.  After confirmation of all final study 
eligibility requirements and obtaining proper informed consent, open-label study 
medication (sufficient supply of bottles at appropriate dose strengths = 50 mg, 100 mg, 
300 mg) will be dispensed to patients, along with seizure diaries for completion until the 
next study visit (Visit 1 / Month 1).  
10.6. Study Visit 1 (Month 1) 
Patients will return for Study Visit 1 (Month 1). At this visit, the following evaluations will 
be performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Brief Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
12-lead ECG 
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• 
AUA Symptom Index 
• 
PVR Bladder Ultrasound 
• 
Adverse Events 
• 
Concomitant Medication 
• 
Open-Label Study Medication (collect returned medication and dispense new 
medication) 
10.7. Study Visit 1a (Month 2) 
Patients will return for Study Visit 1a (Month 2).  At this visit, clinical laboratory tests, 
consisting of the following hematological evaluations (including a differential) will be 
performed: 
• 
Hemoglobin 
• 
Hematocrit  
• 
RBC Count  
• 
WBC Count  
• 
Platelet count.  
10.8. Study Visit 2 (Month 3) 
Patients will return for Study Visit 2 (Month 3). At this visit, the following evaluations will 
be performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Brief Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
12-lead ECG 
• 
AUA Symptom Index 
• 
PVR Bladder Ultrasound 
• 
Adverse Events 
• 
Concomitant Medication 
• 
QOLIE-31-P Questionnaire (completed by patient) 
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• 
Open-Label Study Medication (collect returned medication and dispense new 
medication) 
10.9. Study Visit 2a (Month 4) 
Patients will return for Study Visit 2a (Month 4).  At this visit, clinical laboratory tests, 
consisting of the following hematological evaluations (including a differential) will be 
performed: 
• 
Hemoglobin 
• 
Hematocrit  
• 
RBC Count  
• 
WBC Count  
• 
Platelet count.  
10.10. Study Visit 3 (Month 6) 
Patients will return for Study Visit 3 (Month 6). At this visit, the following evaluations will 
be performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Brief Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
12-lead ECG 
• 
Adverse Events 
• 
Concomitant Medication 
• 
QOLIE-31-P Questionnaire (completed by patient) 
• 
Open-Label Study Medication (collect returned medication and dispense new 
medication) 
10.11. Study Visit 3a (Month 8) 
Patients will return for Study Visit 3a (Month 8).  At this visit, clinical laboratory tests, 
consisting of the following hematological evaluations (including a differential) will be 
performed: 
• 
Hemoglobin 
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• 
Hematocrit  
• 
RBC Count  
• 
WBC Count  
• 
Platelet count.  
10.12. Study Visit 4 (Month 9) 
Patients will return for Study Visit 4 (Month 9). At this visit, the following evaluations will 
be performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Brief Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
12-lead ECG 
• 
Adverse Events 
• 
Concomitant Medication 
• 
QOLIE-31-P Questionnaire (completed by patient) 
• 
Open-Label Study Medication (collect returned medication and dispense new 
medication) 
10.13. Study Visit 4a (Month 10) 
Patients will return for Study Visit 4a (Month 10).  At this visit, clinical laboratory tests, 
consisting of the following hematological evaluations (including a differential), will be 
performed: 
• 
Hemoglobin 
• 
Hematocrit  
• 
RBC Count  
• 
WBC Count  
• 
Platelet count.  
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10.14. Study Visit 5 (Month 12) 
Patients will return for Study Visit 5 (Month 12). At this visit, the following evaluations will 
be performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Complete Physical and Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
Serum Pregnancy Test 
• 
12-lead ECG 
• 
AUA Symptom Index 
• 
PVR Bladder Ultrasound 
• 
Adverse Events 
• 
Concomitant Medication 
• 
QOLIE-31-P Questionnaire (completed by patient) 
• 
Open-Label Study Medication (collect returned medication and dispense new 
medication) 
10.15. Study Visits after the First Year 
After the first year of open-label extension study, the study visits will occur every 4 
months (3 visits per year), and will continue until retigabine is approved and 
commercially available, or until the program is discontinued.  The assessments for the 
first 2 study visits of each year will be identical, and the assessments for the last study 
visit of each year will be identical.  To provide guidance, the following study visits and 
assessments will be performed during the second and third years of the open-label 
extension study: 
10.15.1. Visit 6 (Month 16) 
Patients will return for Study Visit 6 (Month 16), 4 months after Visit 5.  At this visit, the 
following evaluations will be performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Brief Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
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• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
Adverse Events 
• 
Concomitant Medication 
• 
Open-Label Study Medication (Collect returned medication and dispense new 
medication) 
10.15.2. Visit 7 (Month 20) 
Patients will return for Study Visit 7 (Month 20).  At this visit, the following evaluations 
will be performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Brief Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
Adverse Events 
• 
Concomitant Medication 
• 
Open-Label Study Medication (Collect returned medication and dispense new 
medication) 
10.15.3. Visit 8 (Month 24) 
Patients will return for Study Visit 8 (Month 24).  At this visit, the following evaluations 
will be performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Complete Physical and Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
Serum Pregnancy Test 
• 
12-lead ECG 
• 
Adverse Events 
• 
Concomitant Medication 
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• 
QOLIE-31-P Questionnaire (completed by patient) 
• 
Open-Label Study Medication (collect returned medication and dispense new 
medication) 
10.15.4. Visit 9 (Month 28) 
Patients will return for Study Visit 9 (Month 28).  At this visit, the following evaluations 
will be performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Brief Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
Adverse Events 
• 
Concomitant Medication 
• 
Open-Label Study Medication (Collect returned medication and dispense new 
medication) 
10.15.5. Visit 10 (Month 32) 
Patients will return for Study Visit 10 (Month 32).  At this visit, the following evaluations 
will be performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Brief Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
Adverse Events 
• 
Concomitant Medication 
• 
Open-Label Study Medication (Collect returned medication and dispense new 
medication) 
10.15.6. Visit 11 (Month 36) 
Patients will return for Study Visit 11 (Month 36).  At this visit, the following evaluations 
will be performed: 
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• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Complete Physical and Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
Serum Pregnancy Test 
• 
12-lead ECG 
• 
Adverse Events 
• 
Concomitant Medication 
• 
QOLIE-31-P Questionnaire (completed by patient) 
• 
Open-Label Study Medication (collect returned medication and dispense new 
medication) 
10.16. Tapering Period 
All patients who discontinue early from study treatment during the open-label extension 
study will have their study medication tapered over a 3-week period, reducing their daily 
dose by one-third per week, and return immediately for a final visit. The patients will be 
instructed to take the tablets from their existing study medication bottles and to follow 
this tapering procedure: 
• 
During the first week of tapering, patients will no longer take the afternoon dose. 
• 
During the second week of tapering, patients will no longer take the morning and 
the afternoon doses. 
• 
During the third week of tapering, patients will take no study medication (but will 
continue their existing background AEDs).   
During the first year, these patients should then return for a final visit to complete all 
assessments and evaluations scheduled for Study Visit 5. During the second year, these 
patients should then return for a final visit to complete all assessments and evaluations 
scheduled for Study Visit 8. During the third year, these patients should then return for a 
final visit to complete all assessments and evaluations scheduled for Study Visit 11 
(Refer to Study Flow Chart in Appendix A).  
During the tapering period, a new background AED should not be added until after the 
patient’s final visit unless clinically necessary for patient safety. Unused current study 
medication bottles will be collected to ascertain compliance. Current study seizure 
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diaries will be collected and reviewed. Concomitant medications and AED usage will be 
documented, and adverse events will be recorded.  
10.17. Replacement of Patients 
Patients withdrawn from the study will not be replaced. 
10.18. Unscheduled Visits 
Unscheduled visits may be performed if required for assessments of laboratory 
parameters or clinical safety. 
10.19. Laboratory Procedures 
All clinical safety laboratory determinations will be performed by Quintiles Central 
Laboratory Services. The study staff will send the samples to the appropriate address 
(provided in the Central Laboratory Manual) by shipping them in the laboratory kits 
supplied by Quintiles Central Laboratory. Central laboratory reports will be sent to the 
Investigator for evaluation.  
An Investigator may choose to use a local laboratory to evaluate a potential adverse 
event. However, for the purpose of this study, data from local laboratories will not be 
recorded or used in the analysis of safety. The Sponsor will not cover costs associated 
with the use of a local laboratory. 
10.20. Early Termination / Withdrawal Visits 
The Principal Investigator may discontinue a patient from the study for any of the 
following reasons: the patient no longer meets eligibility criteria, it is in the patient’s best 
interest, patient preference, concurrent illness, noncompliance, etc. Patients will be 
informed prior to study entry that they are free to withdraw from the study at any time 
and for any reason. If a patient is discontinued from the study, the Investigator will 
immediately notify the Sponsor or the site CRA of the withdrawal. 
Patients who withdraw from the study prior to completion for any reason (adverse event, 
withdrew consent, etc.) will have their study medication tapered over a 3-week period, 
reducing their daily dose by one-third per week and then return for a final visit.  Patients 
who discontinue early during the first year of the open-label extension study will 
complete all assessments and evaluations scheduled for Study Visit 5.  Patients who 
discontinue early during the second year of the open-label extension study will complete 
all assessments and evaluations scheduled for Study Visit 8.  Patients who discontinue 
early during the third year of the open-label extension study will complete all 
assessments and evaluations scheduled for Study Visit 11 (Refer to Study Flow Chart in 
Appendix A). 
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10.20.1. Reasons for Withdrawal 
Patients are free to discontinue their participation in the study at any time and without 
prejudice to further treatment at their local site. The Investigator must withdraw any 
patient from the study if that patient requests to be withdrawn.   
Patients withdrawn from the study will not be replaced, regardless of the reason for 
withdrawal. The patient’s participation in this study may be discontinued due to the 
following reasons: 
• 
Patient experiences an intolerable AE. 
• 
Investigator decides patient has an “unsatisfactory response – efficacy.” 
• 
Patient becomes pregnant. 
• 
Patient is unwilling or unable to continue the study. 
• 
Patient is non-compliant with study procedures. 
• 
Patient needs medication not allowed in the protocol. 
• 
Any clinically significant change in patient’s medical condition. 
• 
Persistent ALT or aspartate aminotransferase (AST) above 3 times the ULN; will 
be confirmed by repeating laboratory assessment within 1 week. 
• 
ALT or AST levels are above 5 times the ULN at any time during the study. 
• 
Confirmed QTc prolongation defined as QTc (Bazett’s) >500 msec or an increase 
in QTc (Bazett’s) of >60 msec from baseline. 
• 
Investigator decides that withdrawal from the study is in the best interest of the 
patient. 
• 
Request of the Sponsor 
• 
Hematological reasons or infections – for all such patients, the investigator shall 
report these in an expedited manner, whether or not they are considered serious 
or unexpected. 
10.20.2. Handling of Withdrawals 
If a patient is withdrawn from the study either at the patient’s request or at the 
Investigator’s decision or the patient fails to return, every effort should be made to 
determine the reason.  This information will be recorded on the patient’s case report 
form (CRF) and recorded by IVRS.  
All patients who withdraw from the study prematurely, regardless of cause, should have 
their study medication tapered over a 3-week period, reducing their daily dose by one-
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third per week, and follow the tapering procedures outlined in Section 9.12 (Tapering 
Period). 
It is important to obtain follow up data for any patient withdrawn because of an AE, 
abnormal laboratory test, or ECG finding.  In any case, every effort must be made to 
undertake safety follow up procedures. 
11. STATISTICAL MEASUREMENTS, EVALUATIONS AND 
ANALYTICAL METHODS 
11.1. Assessment of Efficacy 
Monthly total seizure rates will be calculated for the entire open-label part of Study VRX-
RET-E22-304 and described statistically. Monthly total seizure rates observed during the 
open-label extension period will be compared to the monthly total seizure rates observed 
during the Baseline phase of the double-blind study VRX-RET-E22-302. The percent 
change in monthly total seizure rates from the Baseline phase will be classified into <0, 
[0, 25), [25, 50), [50, 75), [75, 100] and described. The responder rate during the open-
label study (defined as a reduction in seizure frequency ≥50%) will also be summarized 
using descriptive statistics.  
The number of seizure free days, in percent to the individual duration of the open-label 
treatment, will be calculated and summarized using descriptive statistics. This 
percentage will be classified into [0, 25), [25, 50), [50, 75), [75, 95), [95,100), [=100] and 
described statistically.  
All-cause withdrawal rates will be calculated as a percentage and respective "times to 
event" will be described by a Kaplan-Meier survival curve. Specific reasons for 
withdrawal will also be described separately. 
This is an open-label extension study with the emphasis on safety.  Efficacy is not the 
primary objective of this study unlike the double-blind study VRX-RET-E22-302.  
Descriptive statistics of efficacy measures such as number of patients, mean, standard 
deviation, median, minimum and maximum will be provided for continuous variables.  
The number and percentages in each category will be presented for categorical data.  
The pairwise t-test will be used to assess whether the retigabine treatment remains 
effective in the open-label extension study if necessary.  The pairwise t-test may be 
sorted by the geographic region [Central/Eastern Europe vs. Rest of World (ROW)]. The 
safety assessments will use essentially the same descriptive statistics and pairwise t-test 
as mentioned above for efficacy.  The complete details of efficacy analyses will be 
described in the Statistical Analysis Plan. 
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11.2. Assessment of Safety 
Adverse events (AEs) will be monitored from the start of this extension study (informed 
consent provided by patient at the Baseline visit) until 30 days after administration of the 
last dose of study drug (end of study drug taper-off). Treatment-emergent adverse 
events (TEAEs) will be summarized with respect to overall incidence, as well as severity 
and relationship of the AEs to the study drugs.  AEs that result in dose modification, 
discontinuation of the study drug, or serious adverse events will also be summarized  
AEs with onset after the initiation of study drug and within 30 days after the last dose of 
study drug may be considered treatment-emergent. This will include any AE with onset 
prior to initiation of study drug that increased in severity during the treatment period. All 
reported AEs including those with onset more than 30 days after the last dose of study 
drug will be included in the data listings. 
Abnormal changes in laboratory parameters that are not disease-related will be 
monitored and recorded throughout the study.  
All adverse events will be encoded according to MedDRA 8.0.  Treatment emergent 
adverse events (TEAE) will be analyzed, i.e. all adverse events starting or worsening 
between start of long-term extension study up to 30 days after end of study drug taper-
off. Incidences on preferred term and body system basis will be calculated for all TEAEs. 
Different categories for causality will be recorded in the CRFs, and these 4 categories 
(DEFINITE, PROBABLE, POSSIBLE, and NOT RELATED) are defined in Section 11.3 
(Criteria for Determining Relationship to Study Drug) of this protocol. 
In addition, all SAEs and all AEs leading to premature discontinuation will be presented 
as separate listings. TEAE from both studies (double-blind and open-label extension) will 
be combined, i.e. each patient will be counted just once (with patient’s respective TEAE). 
Other safety evaluations, such as vital signs, physical and neurological examinations, 
laboratory variables, ECG variables, post-void residual bladder ultrasound, and AUA 
symptom index will be analyzed descriptively. 
Besides descriptive statistics of the safety evaluations will be presented, the incidence of 
TEAEs will be compared across treatment group using Fisher’s Exact test, only for those 
events with an incidence of ≥ 5% over all treatment groups.  Fisher’s Exact test will be 
applied if necessary for other safety evaluations (vital signs, physical and neurological 
examinations, laboratory variables, etc.). QTc interval prolongations will be examined by 
using both Bazett’s and Fridericia’s QT correction formulas. The complete details of 
safety analyses will be described in the Statistical Analysis Plan. 
11.3. Determination of Sample Size 
Not applicable for this long-term extension study. 
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11.4. Additional Statistical Considerations 
11.4.1. 
Analysis Population 
The safety population will include all patients who successfully complete the Transition 
phase of Study VRX-RET-E22-302 and were included in this long-term study. The 
Transition phase is the phase of Study VRX-RET-E22-302 during which patients were 
adjusted to a 300 mg TID dose. No other population for analysis is defined for this long-
term extension. 
11.4.2. 
Handling of Missing Data 
No imputation will be made for missing data in the safety analyses, with the exception of 
incomplete date variables regarding adverse events onset date that is necessary for 
defining treatment-emergent adverse events. More details on imputation of partial dates 
will be provided in the statistical analysis plan.  
12. ADVERSE EVENTS 
An adverse event (AE) is defined as any untoward clinical occurrence in a patient 
administered a pharmaceutical drug product that does not necessarily have a causal 
relationship with the study drug. An AE can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom or disease 
temporarily associated with the use of a drug product, whether or not related to the drug 
product.  
The presence or occurrence of any of those clinical manifestations and/or alterations in 
clinical laboratory test results that are either present before participation in this study or 
that are part of the normal fluctuations or progression of their pre-study health state, will 
not engender an AE report to the health authorities. Clinical manifestations and/or 
abnormal laboratory values measured during the study that are a sign of worsening of 
the patient’s pre-study health status or that are new findings may, if clinically relevant, be 
an AE reportable to the health authorities. Abnormal laboratory values represent adverse 
events when they are indicative of a disease or defect (e.g., reduced hematocrit resulting 
in anemia), necessitate intervention (e.g., administration of packed red blood cells or 
other therapies), or result in dose reduction or permanent discontinuation of the drug 
product. 
Throughout the course of the study, AEs will be monitored and recorded on the patients’ 
source documents and CRFs. The onset, seriousness, intensity, duration, actions taken, 
effect on study drug administration (e.g., discontinuation), the potential relationship to 
the study drug, as well as the date of resolution, if any, will be recorded. 
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12.1. Definition and Grading Intensity 
Serious Adverse Events 
A serious adverse event (SAE) is an event that results in any of the following outcomes: 
• 
Death. 
• 
Life-threatening adverse experience. 
• 
Hospitalization (unplanned hospital stay) or prolongation of existing 
hospitalization. 
• 
Persistent or significant disability/incapacity. 
• 
Congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening or require 
hospitalization may be considered serious adverse events when, based on appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
Planned hospitalization or surgery for a condition present prior to the participant’s 
enrollment in the study will not meet the definition of an SAE. 
12.2. Intensity 
The relationship to the study drug and the intensity of an AE should be assessed by the 
Investigator using the following guidelines: 
MILD 
= 
Causing no limitation of usual activities; the patient may 
experience slight discomfort. 
MODERATE 
= 
Causing some limitation of usual activities; the patient may 
experience annoying discomfort; may warrant intervention. 
SEVERE 
= 
Causing inability to carry out usual activities; the patient may 
experience intolerable discomfort or pain; warrants intervention. 
12.3. Criteria for Determining Relationship to Drug 
The Investigator should assess the relationship of the adverse event to the study drug 
according to the following guidelines: 
DEFINITE 
= 
An event that follows a reasonable temporal sequence from 
administration of the drug or in which the drug level has been 
established in body fluids or tissue; that follows a known or 
expected response pattern to the suspected drug; and that is 
confirmed by improvement on stopping or reducing the dosage 
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of the drug, and reappearance of the reaction on repeated 
exposure. 
PROBABLE 
= 
An event that follows a reasonable temporal sequence from 
administration of the drug; that follows a known or expected 
response pattern to the suspected drug; that is confirmed by 
stopping or reducing the dosage of the drug; and that could not 
be reasonably explained by the known characteristics of the 
patient’s clinical state. 
POSSIBLE 
= 
An event that follows a reasonable temporal sequence from 
administration of the drug; that follows a known or expected 
response pattern to the suspected drug; but that could readily be 
produced by a number of other factors. 
NOT RELATED = 
Any event that does not meet the above criteria. 
12.4. Reporting of Adverse Events 
All AEs should be recorded on the appropriate CRFs. All SAEs, whether or not deemed 
drug-related or expected, must be recorded on the CRFs and SAE forms and reported 
by the Investigator to the CRO (Quintiles Pharmacovigilance) assigned by the Sponsor 
within 24 hours by telephone and facsimile. 
Complete details of SAE contact information for Quintiles Pharmacovigilance will be 
provided to sites in each of the participating countries in the Study Reference Manual. 
A written report for an SAE must follow within 24 hours of the initial notification, including 
a full description of the event and any sequelae. This includes events that occur while 
enrolled in the study or within the Follow-Up Period. The Investigator shall comply with 
all applicable regulations and report all SAEs according to the requirements of their 
Institutional Review Board (IRB), Independent Ethics Committee (IEC) or Research 
Ethics Board (REB).  
12.4.1. 
Adverse Events Follow-Up  
AEs will be recorded from the start of this extension study (informed consent provided by 
patient at the Baseline visit) until 30 days after administration of the last dose of study 
medication (end of study medication taper-off). All post-treatment events will be collected 
through spontaneous reporting by the patient. All AEs and SAEs will be followed until the 
event resolves, the condition stabilizes, the event is otherwise explained, or the patient is 
lost to follow up. The Investigator is responsible for ensuring that follow up includes any 
supplemental investigations as may be indicated to elucidate the nature and/or causality 
of the AE.  This may include additional laboratory tests or investigations, 
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histopathological examinations, or consultation with other health care professionals, as 
is practical. 
13. DOSE MODIFICATIONS 
Patients will be treated with 600-1200 mg/day of retigabine as an adjunct therapy to their 
current antiepileptic medications (AEDs) or vagal nerve stimulation as established in 
Study VRX-RET-E22-302. 
If, in the opinion of the Investigator, the patient was not receiving the maximum effective 
dose, the dose could be increased in weekly intervals of 150 mg/day, up to a maximum 
of 1200 mg daily (i.e., 400 mg TID). If adverse events considered to be secondary to 
retigabine occur, the total daily dose could be reduced by 150 mg/day every week, at 
Investigator discretion, as long as the dose is within 600-1200 mg/day. 
After the patient has entered open-label treatment, the Investigator may add new AEDs, 
as long as these are approved AEDs. In addition, the existing background AED therapy 
can be adjusted to achieve the best efficacy/safety ratio, as needed, per Investigator 
discretion. If necessary, in the Investigator’s judgment, all background AEDs can be 
discontinued to achieve monotherapy with retigabine. 
Patients who permanently discontinue open-label treatment will have their dose tapered 
by one-third every week. 
If a patient experiences a serious adverse event that is categorized to be “life-
threatening,” all study medication must be discontinued immediately. 
All dose modifications and reason(s) must be documented in the patient’s source 
documents and the CRF. 
14. MONITORING 
The Sponsor or designee will monitor this clinical trial through visits scheduled to check 
the adequacy of staff and facilities, and to ensure adherence to the protocol, study 
procedures and applicable regulations. The clinical monitor will also assess proper CRF 
completion and retention. The Investigator and clinical staff are expected to allocate 
sufficient time to permit adequate review of the study’s progress. The Investigator will 
permit trial-related monitoring, audits, IRB/IEC review and regulatory inspection(s), 
providing direct access to source data/documents. 
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15. QUALITY ASSURANCE AND QUALITY CONTROL 
The Sponsor or designee will implement and maintain quality assurance and quality 
control systems with Standard Operating Procedures (SOPs) to ensure that this clinical 
trial is conducted and data are generated, documented (recorded) and reported in 
compliance to the protocol, Good Clinical Practice (GCP) standards, ICH and other 
applicable regulations. 
The Sponsor is responsible for securing agreement among collaborating parties to 
ensure direct access to clinical-trial-related sites and material to ensure that all data are 
reliable and have been processed correctly. 
16. DRUG ACCOUNTABILITY 
The Investigator must maintain accurate records of the study medication received from 
the Sponsor, including date received, number of units received and lot number. The 
Investigator must also ensure that the drug supplies are kept secured and accounted for 
with access limited to those authorized by the Investigator. The study coordinator or 
designee must maintain accurate records of all study medication received to be able to 
reconcile the dispensing logs at the end of the study. The study drug records must be 
readily available for inspection by the study monitor and/or auditor. No medication (new 
or used) can be returned to the Sponsor (or its designee) or disposed of at the research 
unit until the Sponsor’s clinical monitor has verified the accuracy of the study medication 
records at the site and indicated whether the medication should be destroyed at the site 
or returned to the Sponsor (or its designee), in which case the study monitor must 
indicate the name and address of the individual to whom the returned materials should 
be shipped. 
17.  LABELING AND PACKAGING OF STUDY MEDICATION 
The study drug will be packaged and labeled in a manner consistent with the study 
design and applicable regulations. The study drug shall be identified as an 
investigational compound. The study protocol number will be identified on the unit label. 
Designated site personnel shall record the drug unit on the drug dispensing logs when 
the study drug is dispensed. 
Each bottle of retigabine tablets (50 mg, 100 mg, or 300 mg per tablet) will be labeled 
with the protocol number, a unique package number, the name of the study medication, 
the use-by date, the Valeant address, and any additional information required by local 
regulations.  In addition, spaces will be included for recording patient number/initials, 
visit number, and dated dispensed. Specific dosage instructions will be provide 
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separately to the patient.  A sufficient supply of study medication will be provided to each 
site for completion of trial, based on the number of patients enrolled, study visit 
schedule, and the daily doses of patients. 
All study medication will be dispensed by the pharmacy or an appropriately qualified 
member of the study staff assigned by the Principal Investigator to this task. 
18. DATA HANDLING AND RECORDKEEPING 
18.1. Records 
The Investigator must maintain all documents and records, copies or originals, relating to 
the conduct of this trial. This documentation includes, but is not limited to protocols, 
CRFs, advertising for patient participation, AE reports, patient source data, 
correspondence with health authorities and IRB/IEC/REB, consent forms, Investigator’s 
curriculum vitae, monitor visit logs, laboratory reference ranges and laboratory 
certification or quality control procedures and laboratory director curriculum vitae. The 
Investigator and affiliated institution should maintain the trial documents as required by 
the applicable regulations. The Investigator and affiliated institution should take 
measures to prevent accidental or premature destruction of documents. Clinical trial 
documents must be kept in the clinical site’s archives indefinitely, unless written 
authorization is obtained from the Sponsor. 
Federal regulations require that records of drug disposition, CRFs, and all reports of this 
investigation shall be retained by the Investigator for a minimum of 15 years after 
notification by Valeant that the regulatory authorities have been notified of the study's 
termination, or 2 years after approval of the marketing application.  If the Investigator is 
unable to retain the study documents for the required amount of time, Valeant must be 
informed of the individual who will be assuming this responsibility.  These documents 
shall be retained for a longer period, however, if required by applicable regulatory 
requirement(s) or if needed by the Sponsor. 
18.2. Case Report Forms 
All entries on a CRF are ultimately the responsibility of the Investigator, who is expected 
to review each form for completeness, accuracy and legibility before signing. All forms 
must be filled out by using black ink. Errors should be lined out but not obliterated and 
the correction inserted, initialed, dated and an explanation provided (if not evident). A 
CRF must be completed for each participant who has given informed consent. The 
CRFs and source documents must be made available to the study monitor for review at 
the time of the monitoring visits. 
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19. INSTITUTIONAL REVIEW BOARD 
This study is to be conducted in accordance with Institutional Review Board (IRB) 
regulations (US 21 CFR, Part 56) or applicable Independent Ethics Committee (IEC) 
regulations. The IRB/IEC must review and approve the following documents, if 
applicable: 
• 
Trial protocol and amendment(s). 
• 
Written informed consent form(s) and consent form updates. 
• 
Patient recruitment procedures (e.g., advertisements). 
• 
Written information to be provided to patients. 
• 
Investigator’s Brochure (IB) and available safety information. 
• 
Information about payments and compensation available to patients. 
The IRB/IEC approval should be in writing, clearly identifying the trial, the documents 
reviewed including informed consent and date of the review. The Investigator has the 
responsibility to provide the Sponsor with the written IRB/IEC approval prior to initiating 
any study-related procedures. The Investigator also has the responsibility to inform the 
IRB/IEC of serious and unexpected AEs and provide the IRB/IEC with a final report upon 
study completion.  
20. COMPLIANCE WITH THE DECLARATION OF HELSINKI 
This study is to be conducted in compliance with the Declaration of Helsinki (Appendix 
C). 
21. INFORMED CONSENT 
Prior to participation in a study, the patient or patient’s legal representative must sign an 
IRB/IEC approved written informed consent form. The approved written informed 
consent must abide to all applicable laws in regards to the safety and confidentiality of 
the patients. To obtain and document informed consent, the Investigator should comply 
with applicable regulations; adhere to GCP standards and the ethical principles in the 
Declaration of Helsinki (Appendix C). 
The language in the oral and written information about the trial, including the written 
informed consent form should be as non-technical as practical and should be 
understandable to the patient or patient’s legal representative and the impartial witness, 
where applicable. Before informed consent is obtained, the Investigator should provide 
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the patient or patient’s legal representative ample time and opportunity to inquire about 
the trial and to decide whether or not to participate. 
All questions about the trial should be answered to the satisfaction of the patient or the 
patient’s legal representative. The written informed consent form should be signed and 
personally dated by the patient or patient’s legal representative, and by the person who 
conducted the informed consent discussion. Patients will be informed that participation is 
voluntary and that he/she can withdraw from the study at any time. A signed copy of the 
consent form must be given to the patient, and this fact will be documented in the CRFs. 
22. CHANGES TO THE PROTOCOL 
The Investigator shall not implement any deviation or change to the protocol without 
approval by the Sponsor and prior review and documented approval and favorable 
opinion from the IRB/IEC/REB. The only exception is when it is necessary to eliminate 
immediate hazards to study patients or when changes involve only logistical or 
administrative aspects of the study (e.g., change in monitors, change in phone 
numbers). 
Although the Sponsor has every intention of completing the study, the Sponsor reserves 
the right to discontinue the study at any time for clinical or administrative reasons. 
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23. REFERENCES 
1. 
Rostock A, Tober C, Rundfeldt C, Bartsch R, Engel J, Polymeropoulos EE, et al. 
D-23129: a new anticonvulsant with a broad spectrum activity in animal models 
of epileptic seizures. Epilepsy Res, 1996;23: 211-23. 
2. 
Tober C, Rostock A, Rundfeldt C, Bartsch R.  D-23129: a potent anticonvulsant 
in the amygdala kindling model of complex partial seizures. Eur J Pharmacol, 
1996; 303: 163-9. 
3. 
Armand V, Rundfeldt C, Heinemann U.  Effects of retigabine (D-23129) on 
different patterns of epileptiform activity induced by 4-aminopyridine in rat 
entorhinal cortex hippocampal slices. Naunyn Schmiedebergs Arch Pharmacol, 
1999;359: 33-9. 
4. 
Armand V, Rundfeldt C, Heinemann U.  Effects of retigabine (D-23129) on 
different patterns of epileptiform activity induced by low magnesium in rat 
entorhinal cortex hippocampal slices. Epilepsia, 2000;41: 28-33. 
5. 
Wang HS, Pan Z, Shi W, Brown BS, Wymore RS, Cohen US, et al.  KCNQ2 and 
KCNQ3 potassium channel subunits: molecular correlates of the M-channel. 
Science, 1998;282: 1890-3. 
6. 
Rundfeldt C, Netzer R.  The novel anticonvulsant retigabine activates M-currents 
in Chinese hamster ovary-cells transfected with human KCNQ2/3 subunits. 
Neurosci Lett, 2000;281: 73-6. 
7. 
Main MJ, Cryan JE, Dupere JR, Cox B, Clare JJ, Burbidge SA, et al.  Modulation 
KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. Mol 
Pharmacol, 2000;58: 253-62. 
8. 
Wickenden AD, Yu WF, Zou A, Jegla T, Wagoner PK, et al.  Retigabine, a novel 
anticonvulsant, enhances activation of KCNQ2/Q3 potassium channels. Mol 
Pharmacol, 2000;58: 591-600. 
9. 
Wickenden AD, Zou AR, Wagoner PK, Jegla T.  Characterization of KCNQ5/Q3 
potassium channels expressed in mammalian cells. Br J Pharmacol, 2001;132: 
381-4. 
10. 
Hirsch E, De Saint-Martin A, Marescaux C.  Benign neonatal familial convulsions: 
a model of idiopathic epilepsy. Rev Neurol (Paris), 1999;155: 463-7. 
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11. 
Rundfeldt C, Netzer R.  Investigation into the mechanism of action of the new 
anticonvulsant retigabine. Interaction with GABAergic and glutamatergic 
neurotransmission and with voltage gated ion channels. Arzneimittelforschung, 
2000;50: 1063-70. 
12. 
Kapetanovic IM, Rundfeldt C.  A new anticonvulsant compound. CNS Drug Rev, 
1996;2: 308-21. 
13. 
White HS, Wolf HH, Woodhead JH, Kupferberg HJ. The National Institutes of 
Health Anticonvulsant Drug Development Program: Screening for Efficacy. 
Antiepileptic Drug Development. Advances in Neurology, Vol. 6. edited by J 
French, I Leppik, and M Dichter. Lippincott-Raven Publishers, Philadelphia, PA, 
1998, pp 29-39. 
14. 
 Effect of D-23129 against amygdala kindled seizures. Report #: D-
23129-FP0295, 1995. 
15. 
 D23129: Investigation of possible abuse potential. Report #: D-23129-
1995. 
16. 
 D-23129, GKE-841: Single dose oral (gavage) 
toxicokinetic study in mice. Report #: D-23129-9321020016, 1999. 
17. 
 Amended document: D-23129: Absolute systemic bioavailability and 
pharmacokinetics following single oral or i.v. administration to Wistar rats. Report 
#: D-23129-FBDD0795, 1998. 
18. 
 Amended document: Metabolism of [14C]D-23129 in rats and dogs 
after oral dosing of 8.25 mg/kg. Report #: D-23129/FB20196, 1998. 
19. 
 Exploratory investigations on the in-vivo metabolism of D-23129 in 
plasma of rats and dogs and on metabolite pharmacokinetics in rats. Report #: D-
23129/FBDD0494, 1995. 
20. 
 In vitro and in vivo metabolism of D-23129 in man. Report 
#: D-23129/FB20396, 1996. 
21. 
 Amended document: Pharmacokinetics of D-23129 in rats following a 
single oral dose administration of the 14C-labeled drug. Report #: D-
23129/FBDD1095, 1999. 
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22. 
 Amended Document: D-23129: Pharmacokinetics in Wistar rats 
following single oral administration of [U-14C]D-23129 at 8.25 mg/kg. Report #: 
D-23129/FB20297, 1998. 
23. 
 D-23129: Pharmacokinetics in Beagle dogs following single oral 
administration of [U-14C]D-23129 at 8.25 /kg. Report #: D-23129/FBDD0995a, 
1997. 
24. 
 The effect of valproic acid on retigabine glucuronidation 
in human liver microsomes. Report #: D-23129/FB20100, 2000. 
25. 
 The effect of imipramine or lamotrigine on retigabine 
glucuronidation in human liver microsomes. Report #: D-23129/FB20399, 1999. 
26. 
 Determination of interactions of D-23129 with the antiepileptic 
standards carbamazepine, sodium valproate and phenytoin. Report #: D-
23129/FP0496, 1995. 
27. 
 Interaction of D-23129 with carbamazepine, valproate and phenytoin in 
rats Report #: D-23129/FP129, 1997. 
28. 
 Anticonvulsant and neurotoxic potencies of D-23129 in the 
threshold models in male mice and female rats. Report #: D-23129/FP2495, 
1994. 
29. 
 Electrophysiological effects of RETIGABINE and its monoacetyl 
metabolite WAY-163980 on cat myocytes and dog Purkinje fibers. Report #: D-
23129/1020107, 1999. 
30. 
 Examination of the effects of retigabine on KCNQ1/KCNE1- and on 
HERG-mediated potassium currents receptor subtypes. Report #: D-
23129/FP10500, 1999. 
31. 
 Retigabine: A multiple oral dose cardiovascular study in conscious 
male and female dogs. Report #: D-23129/9321020, 1999. 
32. 
 Effects of retigabine (WAY-143841) on experimental bladder 
instability in the rat. Report #: D-23129/9321020109, 2001. 
33. 
 Testing the acute toxicity after single oral administration in rats. 
Report #: D-23129/3000912460, 1999. 
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34. 
 Amended document: D-23129: 5-Week oral toxicity study after 
repeated administration in rats and subsequent 6-week recovery period. Report 
#: D-23129/3000900540, 1995. 
35. 
 Complete amended document: Retigabine: 
13 week oral (diet) toxicity study in B6C3F1 mice (amended version 1.1). Report 
#: D-23129/3000922904, 2000. 
36. 
 Retigabine: 28-day oral (t.i.d. capsule) toxicity study in dogs. 
Report #: D-23129/9321020031, 2002. 
37. 
 Amended document: Amendment No. 2 to the report: D-
23129: 13-Week oral toxicity study after repeated administration in beagle dogs 
and subsequent 6-week recovery period. Report #: D-23129/3000896861, 1996.  
38. 
 Examination of the influence of D-23129 on the pregnant rat and 
the fetus by oral administration. Report #: D-23129/3000911733, 1998. 
39. 
 Examination of the influence of D-23129 on the pregnant rabbit and 
the fetus by oral administration, Report #: D-23129/3000911722, 1998. 
40. 
 Retigabine: Oral (gavage) perinatal and 
postnatal toxicity study with behavioral and reproductive assessments of 
offspring in rats. Report #: D-23129/9321020048, 2000. 
41. 
 Retigabine: Two-month oral 
(gavage) toxicity study with recovery in juvenile rats. Report #: D-
23129/9321020106, 2000. 
42. 
 Mutagenicity study of DFB-Retigabine-Oxalate in the Salmonella 
Typhimurium reverse Report #: D-23129/9321020151, 2002. 
43. 
 Salmonella typhimurium reverse mutation assay influence of 
Salmonella typhimurium substrains and S-9 batches on mutagenicity data of 
retigabine (batch 9805004) Report #: D-23129/3000922533, 2001. 
44. 
 CHO/HPRT mammalian mutagenicity assay with D-23129.  
Report #: D-23129/3000914286, 1997. 
45. 
 Chromosome aberration assay in human blood lymphocytes with D-
23129. Report #: D-23129/3000914297, 1997. 
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46. 
 Amended document: In vivo bone marrow cytogenetic test of D-
20443 by oral administration to Sprague-Dawley rats (chromosomal analysis), 
(date of report: April 16, 1993). Report #: D-20443/3000893856, 1997. 
47. 
 In vivo mouse bone marrow erythrocyte micronucleus assay with D-
23129. Report #: D-23129/3000914308, 1997. 
48. 
 D-20443: Mouse micronucleus test (single oral administration) 
Report #: D-20443/3000887657, 1992. 
49. 
 Ascending multiple dose tolerance study 
of retigabine (GKE-841) in healthy male subjects - Ascending, double-blind 
(unblinded third part), placebo-controlled multiple-dose study in healthy male 
subjects (Study no: 3065A1-102-US) Report #: D-23129/9359000010, 2001. 
50. 
 Retigabine N-glucuronidation and its potential role in enterohepatic 
circulation. Report #: D-23129/FB23000, 2001. 
51. 
 In vitro and in vivo metabolism of D-23129 in Man. Report 
#: D-23129/FB20396, 1996. 
52. 
 3065A1-205-EU/AU/US:  A randomized, 
double-blind, placebo-controlled, parallel group, multicenter, dose-ranging, efficacy 
and safety study of retigabine (D-23129, GKE-841) administered as add-on 
therapy in subjects with partial epilepsy. Report #: D-23129/9352000001, 2003. 
53. 
Hempel R, Schupke H, McNeilly PJ, et al. Metabolism of retigabine (D-23129, a 
novel anticonvulsant. Drug Metab Disp, 1999; 27:605-612. 
54. 
 D-23129-8001/D-23129-8005 (03065A1-
200-EU/03065A1-201-EU)Efficacy, Tolerability, Safety and Pharmacokinetics/ 
Steady State Kinetics or Orally Administered Retigabine (GKE-841, D-23129) in 
Patients with Partial Onset Seizures. Report #: D023129/ 9352000002.  
55. 
 3065A1-202-US: A multicenter, open-label, 
safety, tolerability and preliminary efficacy study of GKE-841 (RETIGABINE, D-
23129) administered as add-on therapy to subjects with epilepsy currently 
receiving monotherapy with an established anticonvulsant agent. Report #: CSR-
42037, 2002. 
56 
Investigator’s Brochure. Retigabine (D-23129), Valeant Research & 
Development, Edition Number 6, 13 June 2005.  
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Appendix A. Study Flow Chart (REVISED)  
 
Baseline1 
Open-Label Extension – First Year2,3 
Open-Label Extension - Second Year and 
Onward2,3 
V 0 
V 1 
V 1a9 
V 2 
V 2a9 
V 3 
V 3a9 
V 4 
V 4a9 
V 54 
V 6 
V 7 
V 84 
V 9 
V 10 
V 114 
 
Study Procedures 
Mnth 0 
Mnth 
1 
Mnth 
2 
Mnth 
3 
Mnth 
4 
Mnth 
6 
Mnth 
8 
Mnth 
9 
Mnth 
10 
Mnth 
12 
Mnth 
16 
Mnth 
20 
Mnth 
24 
Mnth 
28 
Mnth 
32 
Mnth 
36 
Eligibility/ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical & Neuro 
Exam 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Brief Neuro Exam 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
X 
 
Vital Signs (BP, HR, & 
Temp) & Wt5 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
12 Lead ECG 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
Blood Chem & 
Hematology 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Hematological 
Evaluation 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Urinalysis (including 
Microscopy) 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
AUA Symptom Index7 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
PVR Bladder 
Ultrasound7 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Serum Preg Test6 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Urine Preg Test6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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Baseline1 
Open-Label Extension – First Year2,3 
Open-Label Extension - Second Year and 
Onward2,3 
V 0 
V 1 
V 1a9 
V 2 
V 2a9 
V 3 
V 3a9 
V 4 
V 4a9 
V 54 
V 6 
V 7 
V 84 
V 9 
V 10 
V 114 
Study Procedures 
 
Mnth 0 
Mnth 
1 
Mnth 
2 
Mnth 
3 
Mnth 
4 
Mnth 
6 
Mnth 
8 
Mnth 
9 
Mnth 
10 
Mnth 
12 
Mnth 
16 
Mnth 
20 
Mnth 
24 
Mnth 
28 
Mnth 
32 
Mnth 
36 
Seizure Diary Review 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
AE Evaluation 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant 
Medication 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
QOLIE-31-P 
Questionnaire 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
Dispense OLE Study 
Meds8 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Collect Returned OLE  
Study  Meds 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
1. 
Baseline for the open-label extension study corresponds to the assessments performed at the last visit of the Maintenance phase (Visit 9) of Study VRX-RET-E22-302 for all patients.  The final, 
baseline eligibility assessment for the open-label extension study, including obtaining informed consent and dispensing open-label study medication will be performed at the last visit of the 
Transition phase (Visit 11) of Study VRX-RET-E22-302. 
2. 
Study Visit 1 will have a window range of ±3 days. After Study Visit 1, all remaining study visits will have a window range of ±7 days around that visit day to accommodate individual schedules. 
Each study month will be defined as 30 calendar days. If a patient visit occurs outside the visit window, the study clinical monitor (CRA) should be notified and the reason for the deviation 
noted. An attempt should be made to ensure that the patient returns for subsequent visits on schedule using the last visit of the Transition phase (Visit 11) of Study VRX-RET-E22-302, which 
corresponds to the final, Baseline eligibility visit for the open-label extension study. 
3. 
This open-label extension study will be continued until retigabine is approved and commercially available, or until the program is discontinued, followed by a 3-week tapering period and a 30 
day post-study period for collection of adverse events.  After the first year, the study visits will occur every 4 months (3 visits per year).  After the first year, the assessments for the first 2 study 
visits of each year (e.g. Visits 6, 7, 9 and 10) will be identical, and the assessments for the last study visit of each year (e.g. Visits 8 and 11) will be identical.   
4. 
All patients who discontinue early from study treatment during the open-label extension study will have their study medication tapered over a 3-week period, reducing their daily dose by one-
third per week, and then return for a final visit.  Patients who discontinue early during the first year of the open-label extension study will complete all assessments and evaluations scheduled 
for Study Visit 5.  Patients who discontinue early during the second year of the open-label extension study will complete all assessments and evaluations scheduled for Study Visit 8.  Patients 
who discontinue early during the third year of the open-label extension study will complete all assessments and evaluations scheduled for Study Visit 11.  Also, all adverse events should be 
followed and collected up to until 30 days after administration of the last dose of study drug (end of study drug taper-off). 
5. 
Supine and standing blood pressure, heart rate. 
6. 
In addition to the scheduled pregnancy tests, a pregnancy test should be performed during the study whenever a woman’s menstrual period is 5 days late. 
7. 
The AUA Symptom Index and the PVR bladder ultrasound will only be performed during the first year of the open-label extension study (Visits 1, 2, and 5).   
8. 
Dispensation of study medication is not applicable at the final study visit, if a patient has discontinued early or completed the open-label extension study. 
9. 
Study visits added per FDA comments that the open label extension trial should include more frequent hematological monitoring.  These are now in-line with the hematological  
monitoring frequencies per the VRX-RET-E22-302, double-blind trial.
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Appendix A. Study Flow Chart (ORIGINAL) 
Baseline1 
Open-Label Extension – First Year2,3 
Open-Label Extension - Second Year and Onward2,3 
Visit 0  
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 54 
Visit 6 
Visit 7 
Visit 84 
Visit 9 
Visit 
10 
Visit 
114 
Study Procedures 
Month 0 
Month 
1 
Month 
3  
Month 
6 
Month 
9 
Month 
12 
Month 
16 
Month 
20 
Month 
24 
Month 
28 
Month 
32 
Month 
36 
Eligibility/Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical and 
Neurological Exam 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
Brief Neurological 
Exam 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
Vital Signs (BP, 
HR, and 
Temperature) and 
Weight5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 Lead ECG 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
Blood Chemistry 
and Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
(including 
Microscopy) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AUA Symptom 
Index7 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
PVR Bladder 
Ultrasound7 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
Serum Pregnancy 
Test6 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
Seizure Diary 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Baseline1 
Open-Label Extension – First Year2,3 
Open-Label Extension - Second Year and Onward2,3 
Visit 0  
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 54 
Visit 6 
Visit 7 
Visit 84 
Visit 9 
Visit 
10 
Visit 
114 
Study Procedures 
Month 0 
Month 
1 
Month 
3  
Month 
6 
Month 
9 
Month 
12 
Month 
16 
Month 
20 
Month 
24 
Month 
28 
Month 
32 
Month 
36 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QOLIE-31-P 
Questionnaire 
X 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
Dispense Open-
Label Study 
Medication8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect Returned 
Open-Label Study 
Medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. 
Baseline for the open-label extension study corresponds to the assessments performed at the last visit of the Maintenance phase (Visit 9) of Study VRX-
RET-E22-302 for all patients.  The final, baseline eligibility assessment for the open-label extension study, including obtaining informed consent and 
dispensing open-label study medication will be performed at the last visit of the Transition phase (Visit 11) of Study VRX-RET-E22-302. 
2. 
Study Visit 1 will have a window range of ±3 days. After Study Visit 1, all remaining study visits will have a window range of ±7 days around that visit day to 
accommodate individual schedules. Each study month will be defined as 30 calendar days. If a patient visit occurs outside the visit window, the study clinical 
monitor (CRA) should be notified and the reason for the deviation noted. An attempt should be made to ensure that the patient returns for subsequent visits 
on schedule using the last visit of the Transition phase (Visit 11) of Study VRX-RET-E22-302, which corresponds to the final, Baseline eligibility visit for the 
open-label extension study. 
3. 
This open-label extension study will be continued until retigabine is approved and commercially available, or until the program is discontinued, followed by a 
3-week tapering period and a 30 day post-study period for collection of adverse events.  After the first year, the study visits will occur every 4 months (3 visits 
per year).  After the first year, the assessments for the first 2 study visits of each year (e.g. Visits 6, 7, 9 and 10) will be identical, and the assessments for the 
last study visit of each year (e.g. Visits 8 and 11) will be identical.   
4. 
All patients who discontinue early from study treatment during the open-label extension study will have their study medication tapered over a 3-week period, 
reducing their daily dose by one-third per week, and then return for a final visit.  Patients who discontinue early during the first year of the open-label 
extension study will complete all assessments and evaluations scheduled for Study Visit 5.  Patients who discontinue early during the second year of the 
open-label extension study will complete all assessments and evaluations scheduled for Study Visit 8.  Patients who discontinue early during the third year of 
the open-label extension study will complete all assessments and evaluations scheduled for Study Visit 11.  Also, all adverse events should be followed and 
collected up to until 30 days after administration of the last dose of study drug (end of study drug taper-off). 
5. 
Supine and standing blood pressure, heart rate. 
6. 
In addition to the scheduled pregnancy tests, a pregnancy test should be performed during the study whenever a woman’s menstrual period is 5 days late. 
7. 
The AUA Symptom Index and the PVR bladder ultrasound will only be performed during the first year of the open-label extension study (Visits 1, 2, and 5).   
8. 
Dispensation of study medication is not applicable at the final study visit, if a patient has discontinued early or completed the open-label extension study.
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Appendix B. Medical Association Declaration of Helsinki 
Ethical Principles for Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended 
by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
Note of Clarification on Paragraph 29 added by the WMA General Assembly, Washington 
2002 
Note of Clarification on Paragraph 30 added by the WMA General Assembly, Tokyo 2004 
 
INTRODUCTION 
1. The World Medical Association has developed the Declaration of Helsinki as a statement 
of ethical principles to provide guidance to physicians and other participants in medical 
research involving human subjects. Medical research involving human subjects includes 
research on identifiable human material or identifiable data. 
2. It is the duty of the physician to promote and safeguard the health of the people. The 
physician's knowledge and conscience are dedicated to the fulfillment of this duty. 
3. The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my patient will be my first consideration," and the International 
Code of Medical Ethics declares that, "A physician shall act only in the patient's interest 
when providing medical care which might have the effect of weakening the physical and 
mental condition of the patient."  
4. Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects. 
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5. In medical research on human subjects, considerations related to the well-being of the 
human subject should take precedence over the interests of science and society. 
6. The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the 
aetiology and pathogenesis of disease. Even the best proven prophylactic, diagnostic, 
and therapeutic methods must continuously be challenged through research for their 
effectiveness, efficiency, accessibility and quality. 
7. In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
8. Medical research is subject to ethical standards that promote respect for all human 
beings and protect their health and rights. Some research populations are vulnerable 
and need special protection. The particular needs of the economically and medically 
disadvantaged must be recognized. Special attention is also required for those who 
cannot give or refuse consent for themselves, for those who may be subject to giving 
consent under duress, for those who will not benefit personally from the research and for 
those for whom the research is combined with care. 
9. Research Investigators should be aware of the ethical, legal and regulatory requirements 
for research on human subjects in their own countries as well as applicable international 
requirements. No national ethical, legal or regulatory requirement should be allowed to 
reduce or eliminate any of the protections for human subjects set forth in this 
Declaration. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
10. It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject. 
11. Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and on adequate laboratory and, where appropriate, 
animal experimentation. 
12. Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
13. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol. This protocol should be 
submitted for consideration, comment, guidance, and where appropriate, approval to a 
specially appointed ethical review committee, which must be independent of the 
Investigator, the sponsor or any other kind of undue influence. This independent 
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committee should be in conformity with the laws and regulations of the country in which 
the research experiment is performed. The committee has the right to monitor ongoing 
trials. The researcher has the obligation to provide monitoring information to the 
committee, especially any serious adverse events. The researcher should also submit to 
the committee, for review, information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 
14. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in 
this Declaration. 
15. Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person. 
The responsibility for the human subject must always rest with a medically qualified 
person and never rest on the subject of the research, even though the subject has given 
consent. 
16. Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to 
the subject or to others. This does not preclude the participation of healthy volunteers in 
medical research. The design of all studies should be publicly available. 
17. Physicians should abstain from engaging in research projects involving human subjects 
unless they are confident that the risks involved have been adequately assessed and 
can be satisfactorily managed. Physicians should cease any investigation if the risks are 
found to outweigh the potential benefits or if there is conclusive proof of positive and 
beneficial results. 
18. Medical research involving human subjects should only be conducted if the importance 
of the objective outweighs the inherent risks and burdens to the subject. This is 
especially important when the human subjects are healthy volunteers. 
19. Medical research is only justified if there is a reasonable likelihood that the populations 
in which the research is carried out stand to benefit from the results of the research. 
20. The subjects must be volunteers and informed participants in the research project. 
21. The right of research subjects to safeguard their integrity must always be respected. 
Every precaution should be taken to respect the privacy of the subject, the confidentiality 
of the patient's information and to minimize the impact of the study on the subject's 
physical and mental integrity and on the personality of the subject. 
22. In any research on human beings, each potential subject must be adequately informed 
of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
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affiliations of the researcher, the anticipated benefits and potential risks of the study and 
the discomfort it may entail. The subject should be informed of the right to abstain from 
participation in the study or to withdraw consent to participate at any time without 
reprisal. After ensuring that the subject has understood the information, the physician 
should then obtain the subject's freely-given informed consent, preferably in writing. If 
the consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed. 
23. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or 
may consent under duress. In that case the informed consent should be obtained by a 
well-informed physician who is not engaged in the investigation and who is completely 
independent of this relationship. 
24. For a research subject who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the Investigator must obtain informed 
consent from the legally authorized representative in accordance with applicable law. 
These groups should not be included in research unless the research is necessary to 
promote the health of the population represented and this research cannot instead be 
performed on legally competent persons. 
25. When a subject deemed legally incompetent, such as a minor child, is able to give 
assent to decisions about participation in research, the Investigator must obtain that 
assent in addition to the consent of the legally authorized representative. 
26. Research on individuals from whom it is not possible to obtain consent, including proxy 
or advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population. The 
specific reasons for involving research subjects with a condition that renders them 
unable to give informed consent should be stated in the experimental protocol for 
consideration and approval of the review committee. The protocol should state that 
consent to remain in the research should be obtained as soon as possible from the 
individual or a legally authorized surrogate. 
27. Both authors and publishers have ethical obligations. In publication of the results of 
research, the Investigators are obliged to preserve the accuracy of the results. Negative 
as well as positive results should be published or otherwise publicly available. Sources 
of funding, institutional affiliations and any possible conflicts of interest should be 
declared in the publication. Reports of experimentation not in accordance with the 
principles laid down in this Declaration should not be accepted for publication. 
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ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
28. The physician may combine medical research with medical care, only to the extent that 
the research is justified by its potential prophylactic, diagnostic or therapeutic value. 
When medical research is combined with medical care, additional standards apply to 
protect the patients who are research subjects. 
29. The benefits, risks, burdens and effectiveness of a new method should be tested against 
those of the best current prophylactic, diagnostic, and therapeutic methods. This does 
not exclude the use of placebo, or no treatment, in studies where no proven 
prophylactic, diagnostic or therapeutic method exists.1 
30. At the conclusion of the study, every patient entered into the study should be assured of 
access to the best proven prophylactic, diagnostic and therapeutic methods identified by 
the study.2 
31. The physician should fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study must never interfere with the 
patient-physician relationship. 
32. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent from 
the patient, must be free to use unproven or new prophylactic, diagnostic and 
therapeutic measures, if in the physician's judgment it offers hope of saving life, re-
establishing health or alleviating suffering. Where possible, these measures should be 
made the object of research, designed to evaluate their safety and efficacy. In all cases, 
new information should be recorded and, where appropriate, published. The other 
relevant guidelines of this Declaration should be followed. 
 
 
1 Note of clarification on paragraph 29 of the WMA Declaration of Helsinki 
The WMA hereby reaffirms its position that extreme care must be taken in making use of a 
placebo-controlled trial and that in general this methodology should only be used in the 
absence of existing proven therapy. However, a placebo-controlled trial may be ethically 
acceptable, even if proven therapy is available, under the following circumstances: 
- Where for compelling and scientifically sound methodological reasons its use is necessary 
to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or 
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- Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor 
condition and the patients who receive placebo will not be subject to any additional risk of 
serious or irreversible harm. 
All other provisions of the Declaration of Helsinki must be adhered to, especially the need 
for appropriate ethical and scientific review. 
 
2 Note of clarification on paragraph 30 of the WMA Declaration of Helsinki 
The WMA hereby reaffirms its position that it is necessary during the study planning process 
to identify post-trial access by study participants to prophylactic, diagnostic and therapeutic 
procedures identified as beneficial in the study or access to other appropriate care. Post-trial 
access arrangements or other care must be described in the study protocol so the ethical 
review committee may consider such arrangements during its review. 
9.10.2004 
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Appendix C. American Urological Association Symptom 
Index 
Reference: 
Barry MJ, et al. (1992). The American Urological Association symptom index for benign 
prostatic hyperplasia. Journal of Urology, 148: 1549–1557. 
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This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
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Appendix D. Protocol Agreement 
PROTOCOL TITLE: 
A multicenter, open-label, long-term, safety, tolerability and efficacy study of retigabine in 
adult epilepsy patients with partial-onset seizures (Extension of study VRX-RET-E22-302). 
 
PROTOCOL NO: 
VRX-RET-E22-304 
This document is a confidential communication of Valeant Pharmaceuticals, North America. 
The authorized Investigator agrees to personally conduct or supervise the conduct of this 
study as outlined in the current protocol. No changes will be made to the protocol without 
prior written approval from Valeant Pharmaceuticals, North America, except to protect the 
safety, rights and welfare of the study participants and always in compliance with all 
applicable Good Clinical Practices (GCP), as well as International Conference on 
Harmonization (ICH) and regulatory requirements. Acceptance of this document constitutes 
the agreement by the Investigator that no unpublished information contained herein will be 
published or disclosed without prior written approval from Valeant Pharmaceuticals, North 
America. 
I have read this protocol in its entirety and agree to conduct the study accordingly. 
 
 
______________________________________________ 
_________________ 
Signature: 
Date 
Principal Investigator 
 
 
______________________________________________ 
Printed Name 
 
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Confidential 
This document contains confidential information, which should not be copied, referred to, released or 
published without written approval from Valeant Research & Development.  
 
 
 
 
Clinical Study Protocol 
Retigabine 
 
A multicenter, open-label, long-term, safety, 
tolerability and efficacy study of retigabine in adult 
epilepsy patients with partial-onset seizures 
(Extension of Study VRX-RET-E22-302) 
 
Protocol Number VRX-RET-E22-304 
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published without written approval from Valeant Research & Development.  
 
 
 
 
1. TITLE PAGE 
STUDY TITLE: 
A multicenter, open-label, long-term, 
safety, tolerability and efficacy study of 
retigabine in adult epilepsy patients with 
partial-onset seizures (Extension of 
Study VRX-RET-E22-302) 
INVESTIGATIONAL PRODUCT: 
Retigabine 
IND NUMBER: 
53,950 
PROTOCOL NUMBER: 
VRX-RET-E22-304 
PHASE: 
3 
SPONSOR: 
Valeant Research & Development  
3300 Hyland Avenue 
Costa Mesa, CA 92626 USA 
Main Office: 
 
FAX: 
 
CONTRACT RESEARCH 
ORGANIZATION (CRO): 
Quintiles, Inc.  
5927 South Miami Blvd. 
Morrisville, NC 27560 
CRO MEDICAL MONITOR: 
 MD 
Quintiles GmbH  
Hugenottenallee 167 
D-63263 Neu-Isenberg, Germany  
Tel: 
 Ext. 
 
Facsimile: 
 
COUNTRIES:  
Western, Central and Eastern Europe, 
Australia, Israel, and South Africa 
 
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2. PROTOCOL SIGN-OFF SHEET 
PROTOCOL TITLE: 
A multicenter, open-label, long-term, safety, 
tolerability and efficacy study of retigabine in 
adult epilepsy patients with partial-onset 
seizures (Extension of Study VRX-RET-E22-
302) 
PROTOCOL NUMBER: 
VRX-RET-E22-304 
VERSION: 
February 10, 2006 
 
 
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3. TABLE OF CONTENTS 
Page 
1. 
Title Page 
2 
2. 
Protocol Sign-Off Sheet 
3 
3. 
Table of Contents 
4 
4. 
List of Abbreviations 
7 
5. 
Study Synopsis 
10 
6. 
Introduction 
14 
6.1. 
Background 
14 
6.2. 
Pharmacology 
15 
6.3. 
Preclinical Safety Studies 
15 
6.4. 
Clinical Studies 
17 
6.5. 
Safety and Tolerability 
18 
6.6. 
Pharmacokinetics 
19 
6.6.1. 
Absorption 
19 
6.6.2. 
Metabolism 
19 
6.6.3. 
Excretion 
19 
7. 
Study Objectives 
19 
8. 
Study Design 
20 
8.1. 
Type of Study 
20 
8.2. 
Study Population 
20 
8.3. 
Number of Study Sites 
20 
8.4. 
Treatment Duration 
20 
8.5. 
Patient Inclusion Criteria 
20 
8.6. 
Patient Exclusion Criteria 
21 
8.7. 
Study Medication 
21 
8.7.1. 
Dosage Schedule and Mode of Administration 
21 
8.7.2. 
Study Drug Storage 
22 
8.7.3. 
Study Drug Returns 
22 
8.7.4. 
Method of Assigning Study Medication to Patients 
22 
8.7.5. 
Discontinuation and Tapering of Study Medication 
23 
8.8. 
Assessment of Compliance 
23 
8.9. 
Concomitant Therapy 
23 
8.9.1. 
Permitted Concomitant Medications 
23 
8.9.2. 
Prohibited Medications 
24 
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8.10. Protocol Violations and Deviations 
24 
9. 
Study Procedures 
24 
9.1. 
Study Flow Chart 
24 
9.2. 
Efficacy Assessments 
25 
9.3. 
Safety Assessments 
26 
9.3.1. 
Vital Sign Measurements and Weight 
26 
9.3.2. 
Physical and Neurological Examinations 
26 
9.3.3. 
Electrocardiograms 
26 
9.3.4. 
Laboratory Assessments 
27 
9.3.5. 
Post-Void Residual (PVR) Bladder Ultrasound 
28 
9.3.6. 
AUA Symptom Index 
28 
9.4. 
Quality of Life Assessments 
29 
9.5. 
Baseline 
29 
9.6. 
Study Visit 1 (Month 1) 
29 
9.7. 
Study Visit 2 (Month 3) 
30 
9.8. 
Study Visit 3 (Month 6) 
30 
9.9. 
Study Visit 4 (Month 9) 
31 
9.10. Study Visit 5 (Month 12) 
31 
9.11. Study Visits after the First Year 
32 
9.11.1. Visit 6 (Month 16) 
32 
9.11.2. Visit 7 (Month 20) 
32 
9.11.3. Visit 8 (Month 24) 
33 
9.11.4. Visit 9 (Month 28) 
33 
9.11.5. Visit 10 (Month 32) 
34 
9.11.6. Visit 11 (Month 36) 
34 
9.12. Tapering Period 
34 
9.13. Replacement of Patients 
35 
9.14. Unscheduled Visits 
35 
9.15. Laboratory Procedures 
35 
9.16. Early Termination / Withdrawal Visits 
36 
9.16.1. Reasons for Withdrawal 
36 
9.16.2. Handling of Withdrawals 
37 
10. 
Statistical Measurements, Evaluations and Analytical Methods 
37 
10.1. Assessment of Efficacy 
37 
10.2. Assessment of Safety 
38 
10.3. Determination of Sample Size 
39 
10.4. Additional Statistical Considerations 
39 
10.4.1. Analysis Population 
39 
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10.4.2. Handling of Missing Data 
39 
11. 
Adverse Events 
39 
11.1. Definition and Grading Intensity 
40 
11.2. Intensity 
40 
11.3. Criteria for Determining Relationship to Drug 
40 
11.4. Reporting of Adverse Events 
41 
11.4.1. Adverse Events Follow-Up 
41 
12. 
Dose Modifications 
42 
13. 
Monitoring 
42 
14. 
Quality Assurance and Quality Control 
43 
15. 
Drug Accountability 
43 
16. 
Labeling and Packaging of Study Medication 
43 
17. 
Data Handling and Recordkeeping 
44 
17.1. Records 
44 
17.2. Case Report Forms 
44 
18. 
Institutional Review Board 
45 
19. 
Compliance with the Declaration of Helsinki 
45 
20. 
Informed Consent 
45 
21. 
Changes to the Protocol 
46 
22. 
References 
47 
Appendix A. 
Study Flow Chart 
52 
Appendix B. 
World Medical Association Declaration of Helsinki 
54 
Appendix C. 
American Urological Association Symptom Index 
60 
Appendix D. 
Protocol Agreement 
61 
 
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4. LIST OF ABBREVIATIONS 
AE 
= 
Adverse event 
AED 
= 
Antiepileptic drug 
ALT 
= 
Alanine aminotransferase 
ANCOVA 
= 
Analysis of covariance 
ANOVA 
= 
Analysis of variance 
APD 
= 
Action potential duration 
AST 
= 
Aspartate aminotransferase 
AUA 
= 
American Urological Association 
AUC 
= 
Area under the curve 
β-HCG 
= 
Beta human chorionic gonadotropin 
BID 
= 
Twice a day 
BMI 
= 
Body mass index 
BP 
= 
Blood pressure 
BUN 
= 
Blood urea nitrogen 
CFR 
= 
Code of Federal Regulations 
CGI 
= 
Clinical global impressions 
CI 
= 
Confidence interval 
Cmax 
= 
Observed maximum plasma concentration 
Cmin 
= 
Observed minimum plasma concentration 
CNS 
= 
Central nervous system 
CPMP 
= 
Committee for Proprietary Medicinal Products 
CRA 
= 
Clinical research associate 
CRF 
= 
Case report form 
CSR 
= 
Clinical study report 
CT 
= 
Computerized tomography 
CV 
= 
Curriculum vitae 
CV% 
= 
Coefficient of variation 
D-20443 
= 
Dihydrochloride salt of retigabine 
ECG 
= 
Electrocardiogram 
EDTA 
= 
Ethylenediaminetetraacetic acid 
EEG 
= 
Electroencephalogram 
EMEA 
= 
European Agency for the Evaluation of Medicinal Products 
FDA 
= 
Food and Drug Administration 
GABA 
= 
Gamma aminobutyric acid  
GCP 
= 
Good Clinical Practice 
hERG 
= 
Human ether-a-go-go related gene 
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HPF 
= 
High power field 
HR 
= 
Heart rate 
ICF 
= 
Informed consent form 
ICH 
= 
International Conference on Harmonization 
IEC 
= 
Independent Ethics Committee 
ILAE 
= 
International League Against Epilepsy 
IND 
= 
Investigational New Drug 
IRB 
= 
Institutional Review Board 
ISE 
= 
Integrated Summary of Efficacy 
ISS 
= 
Integrated Summary of Safety 
ITT 
= 
Intent to treat 
i.v. 
= 
Intravenous 
IVRS 
= 
Interactive Voice Response System 
LFT 
= 
Liver function test 
MAOI 
= 
Monamine oxidase inhibitor 
MedDRA 
= 
Medical Dictionary for Regulatory Activities 
MRI 
= 
Magnetic resonance imaging 
msec 
= 
Milliseconds 
MTD 
= 
Maximum tolerated dose 
N 
= 
Number of patients 
NAT 
= 
N-acetyl transferase 
pH 
= 
Hydrogen Ion Concentration 
PK 
= 
Pharmacokinetics 
PGI 
= 
Patient global impressions 
p.o. 
= 
Oral 
PP 
= 
Per protocol 
PVR 
= 
Post-void residual (bladder ultrasound) 
QD 
= 
Once a day 
QoL 
= 
Quality of Life 
QOLIE-31-P = 
Quality of Life in Epilepsy-Problems Questionnaire 
QTc 
= 
QT correction 
QTcB 
= 
Bazett’s QT correction 
QTcF 
= 
Fridericia’s QT correction 
QTcI 
= 
Individual patient’s QT correction 
RBC 
= 
Red blood cell 
REB 
= 
Research Ethics Board 
SAE 
= 
Serious adverse event 
SAP 
= 
Statistical Analysis Plan 
SD 
= 
Standard deviation 
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SEM 
= 
Standard error of the mean 
SUDEP 
= 
Sudden Unexplained Death in Epilepsy 
t1/2 
= 
Half life 
TdP 
= 
Torsade des Pointes 
TEAE 
= 
Treatment-emergent adverse event 
TID 
= 
Three times a day 
UDPGT 
= 
UDP-glucuronosyltransferase 
UDS 
= 
unscheduled DNA synthesis 
UGT 
= 
uridine diphosphate-glucuronosyltransferase 
ULN 
= 
Upper limit of normal 
URI 
= 
Upper respiratory infection 
UTI 
= 
Urinary tract infection 
Valeant 
= 
Valeant Research & Development 
VNS 
= 
Vagal nerve stimulator 
WBC 
= 
White blood cell 
WHO 
= 
World Health Organization 
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5. STUDY SYNOPSIS 
TITLE: 
A multicenter, open-label, long-term, safety, tolerability and efficacy 
study of retigabine in adult epilepsy patients with partial-onset 
seizures (Extension of Study VRX-RET-E22-302) 
PHASE: 
3 
OBJECTIVES: 
1. Primary: To evaluate the safety and tolerability of long-term 
therapy with retigabine administered as adjunctive therapy in 
adult epilepsy patients with partial-onset seizures, who 
completed the double-blind Study VRX-RET-E22-302.  
2. Secondary: To evaluate efficacy of long-term treatment with 
retigabine and patient quality of life, evaluated through the 
QOLIE-31-P questionnaire. 
STUDY DESIGN: 
This is an open-label extension study of the placebo-controlled, 
double-blind Study VRX-RET-E22-302. Patients will be treated with 
600-1200 mg/day of retigabine as an adjunct therapy to their current 
antiepileptic medications (AEDs) or vagal nerve stimulation as 
established in Study VRX-RET-E22-302. Treatment will be 
continued until retigabine is approved and commercially available, 
or until the program is discontinued, followed by a 3-week tapering 
period and a 30 day post study period for collection of Adverse 
Events (AEs). 
SAMPLE SIZE: 
All patients who complete Study VRX-RET-E22-302 are qualified to 
participate (up to approximately 510 patients). 
NUMBER OF SITES: 
This is a multicenter study involving approximately 55-60 study sites 
in the Western, Central, and Eastern Europe, Australia, Israel, and 
South Africa. 
TREATMENT 
GROUPS: 
All patients will be treated with 600-1200 mg/day of retigabine as an 
adjunct therapy to their current antiepileptic medications (AEDs) or 
vagal nerve stimulation. 
TREATMENT 
DURATION: 
This study will allow the patients who complete Study VRX-RET-
E22-302 to continue with retigabine until the drug is approved and 
commercially available, or until the program is discontinued. 
FORMULATION: 
Retigabine will be supplied by Valeant Research & Development in 
bottles containing tablets in relevant strengths: 50 mg, 100 mg, or 
300 mg. 
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KEY INCLUSION 
CRITERIA: 
1. Patient has successfully completed the Maintenance and 
Transition phases of Study VRX-RET-E22-302 for the treatment 
of partial-onset seizures 
2. Patient is expected to benefit from participation in the study in 
the opinion of the Investigator. 
3. Women of childbearing potential and fertile males have to agree 
to use a medically acceptable method of birth control and 
females had to have a negative serum β-HCG pregnancy test at 
the last visit of the Transition phase of Study VRX-RET-E22-
302. A woman of childbearing potential is defined as a female 
who is biologically capable of becoming pregnant. A medically 
acceptable method of birth control includes an intrauterine 
device in place for at least 3 months, surgical sterilization (e.g. 
tubal ligation), or adequate barrier methods (e.g., diaphragm and 
foam). An oral contraceptive alone is not considered adequate 
for the purpose of this study. 
4. In the opinion of the Investigator, patient is able to understand 
verbal and written instructions and will adhere to all study 
schedules and requirements. 
5. Patient or legal guardian (if applicable) is informed, given ample 
time and opportunity to read and/or understand about his/her 
participation in the study, and has signed and dated the written 
informed consent form. 
KEY EXCLUSION 
CRITERIA: 
1. Patient meets any of the withdrawal criteria in the previous VRX-
RET-E22-302 study or is experiencing an ongoing serious 
adverse event. 
2. Patient is receiving any investigational drug or using any 
experimental device in addition to Retigabine for treatment of 
epilepsy or any other medical condition. 
3. Patient has any other condition that would prevent compliance 
with the study procedures or proper reporting of AEs. 
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EVALUATION 
CRITERIA: 
• 
Efficacy: Patients will keep a seizure diary throughout the study. 
The anticonvulsant efficacy of retigabine will be evaluated by 
comparison of baseline seizure frequency (obtained during the 
8-week baseline period of Study VRX-RET-E22-302) with 
seizure frequency obtained during retigabine therapy in this 
study. The primary efficacy variable will be the percentage 
change in the monthly seizure rate from the baseline phase to 
open-label treatment. The proportion of responders (patients 
experiencing ≥ 50% reduction in seizure frequency) from 
baseline to the open-label treatment phase will also be 
evaluated. 
• 
Safety: Safety will be assessed by measurements of vital signs, 
weight, clinical laboratory evaluations (blood chemistry, 
hematology, and urinalysis), 12-lead ECGs, physical and 
neurological examinations, and evaluations of adverse events. 
Patients will additionally be assessed using the American 
Urological Association Symptom Index to assess the urinary 
voiding function. 
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STATISTICAL 
ANALYSIS: 
The safety population will include all patients who successfully 
complete the Transition phase of Study VRX-RET-E22-302 and 
were included in this long-term study. The Transition phase is the 
phase of Study VRX-RET-E22-302 during which patients were 
adjusted to a 300 mg TID dose of retigabine. No other population for 
analysis is defined for this long-term extension study. 
Assessment of Efficacy: 
"Monthly total partial seizure" as well as "monthly total seizure" rates 
will be calculated for the entire open-label part of Study VRX-RET-
E22-304 and described statistically. 
Baseline monthly total partial seizure rate from Study VRX-RET-
E22-302 will be used for the calculation of difference and % change 
in the open-label study. The % change will be classified into <0, [0, 
25), [25, 50), [50, 75), [75, 100] with a description of the 
frequencies. The responder rate (defined as a reduction in seizure 
frequency ≥50%) is the sum of the upper two classes.   
The number of seizure free days, in percent to the individual 
duration of the open-label treatment, will be calculated and 
described statistically. In addition, frequencies for this percentage 
will be classified into [0, 25), [25, 50), [50, 75), [75, 95), [95,100), 
=100. The most upper class represents completely seizure free 
patients, the next class almost seizure free patients. 
Additional details will be provided in the Statistical Analysis Plan 
(SAP). 
Assessment of Safety: 
All adverse events will be encoded according to MedDRA 8.0. 
Treatment emergent adverse events (TEAE) will be analyzed, i.e. all 
adverse events starting or worsening between the start of the long-
term open-label study up to 30 days after end of taper-off study drug 
at the completion of the open-label study. Incidences on preferred 
term and body system basis will be calculated for all TEAEs. In 
addition, all serious adverse events (SAEs) and all AEs leading to 
premature discontinuation will be presented as separate listings. A 
prospective analysis will be conducted in order to compare the 
results of this study to Study VRX-RET-E22-302. 
TEAE from both studies (double-blind and open-label extension) will 
be combined, i.e. each patient will be counted just once (with 
patient’s respective TEAE). 
Other safety evaluations, such as vital signs, laboratory variables, 
ECG variables, AUA symptom index will be analyzed descriptively. 
Additional details will be provided in the Statistical Analysis Plan 
(SAP). 
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6. INTRODUCTION 
6.1. 
Background 
Epilepsy is among the most common neurological disorders, affecting approximately 50 
million people worldwide.  Classical antiepileptic drugs (AEDs) currently provide satisfactory 
seizure control in approximately 70% of patients; however, the remaining 30% of epilepsy 
patients are refractory to treatment.  The partial onset seizure is the most common type of 
seizure that is uncontrolled in adult patients.  The introduction of new AEDs (e.g., vigabatrin, 
lamotrigine, gabapentin, topiramate, levetiracetam, oxcarbazepine, zonisamide, and 
felbamate) during the last decade has increased therapeutic possibilities.  However, data 
from recent clinical trials demonstrate that none of the newer AEDs provides adequate 
seizure control in all patients.  The treatment of patients that do not respond to current AEDs 
remains a problem and motivates the continued search for compounds with high 
antiepileptic potential and low rates of side effects.  
Retigabine (GKE-841 or D-23129), N-[2-amino-4(4-fluorobenzylamino)-phenyl] carbamic 
acid ethyl ester, is a new chemical entity discovered by ASTA Medica, Germany, and was 
acquired by Valeant Research & Development (Valeant) for development as an AED for the 
treatment of partial onset seizures. It is a deaza analog of flupirtine, currently marketed in 
some regions as a centrally acting analgesic with ancillary muscle relaxing properties. 
Two Phase 3 studies (VRX-RET-E22-301 and VRX-RET-E22-302) to compare the efficacy 
and safety of Retigabine (600 mg/day, 900 mg/day, or 1200 mg/day) to placebo as an 
adjunctive therapy in refractory patients with partial-onset seizures are currently being 
conducted. These studies are randomized, double-blind, placebo-controlled, multi-center, 
parallel-group trials enrolling a total of approximately 790 patients, globally. Because of the 
serious nature of epilepsy, the retigabine clinical program had foreseen that all patients who 
enter and complete a Phase 3 study with retigabine will be given the opportunity to continue 
treatment, if they consent and if the Principal Investigator feels they can benefit from 
continued retigabine treatment. Hence, an open-label extension protocol was designed for 
each double-blind study. 
This study is the open-label extension of the Phase 3 Study VRX-RET-E22-302. VRX-RET-
E22-302 is a randomized, double-blind, placebo-controlled, parallel-group, multicenter, 
study of 900 mg/day and 600 mg/day retigabine versus placebo. During the 4-week titration 
phase patients are titrated to the target dose.  510 patients are expected to be randomized 
to treatment. A 12-week maintenance phase follows. All patients who wish to enter the 
open-label extension protocol will enter a 4-week transition phase in which their dose will be 
titrated to 300 mg TID in order to maintain the blind to the maximum extent. Thereafter, the 
patients could enter this extension study (Study VRX-RET-E22-304).  Patients who do not 
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wish to enter the open-label extension protocol will have their dose tapered over a 3-week 
period. 
6.2. 
Pharmacology 
Retigabine is a novel antiepileptic compound with a broad spectrum of activity and potent 
anticonvulsant properties.1,2,3,4 Retigabine opens specific potassium channels called M 
channels linked to the KCNQ2/3 and KCNQ3/5 heteromultimeres, which are involved in the 
control of the excitability of neuronal cells.5,6,7,8,9 Mutations in these channels were 
understood to be linked to benign neonatal familial convulsions.10 This fact strongly supports 
the experimental evidence that M-channel activation may be a unique and powerful cellular 
target principle for the treatment of epilepsy. Retigabine also has a concentration-dependent 
ancillary mode of action by increasing gamma aminobutyric acid (GABA)-evoked currents.  
These effects, however, were seen at concentrations of 10 µmol/L, whereas the potassium 
channel-opening effects occur at concentrations as low as 0.1 µmol/L.11,12 
Results from preclinical studies revealed that retigabine is effective in a broad range of 
animal models of epileptic seizures. Amygdala kindling is considered the most predictive 
animal model for human complex partial seizures.13 In kindled rats, intraperitoneal or oral 
doses of retigabine as low as 0.01 mg/kg were effective in increasing the threshold for 
induction.14 At a higher dose of 5 mg/kg retigabine also reduced seizure severity, seizure 
duration, and post-discharge duration in fully kindled rats.14 A clear separation between 
antiepileptic and neurotoxic effects is evident in these preclinical models.  In addition, 
preclinical testing has not revealed any tolerance, dependence, or withdrawal liabilities for 
retigabine.15 
Retigabine is rapidly absorbed following p.o. (oral) administration with peak plasma 
concentrations being achieved 1-2 hours after dosing in mice and rats.16,17 The absolute 
bioavailability ranged from 44% to 70%.17 Retigabine is extensively distributed and rapidly 
eliminated from all tissues in rats over a 48- to 72-hour period after dosing.18,19 Retigabine is 
primarily metabolized by acetylation, glucuronidation, and oxidation mechanisms in rats and 
by glucuronidation in dogs. The active N-acetyl metabolite of retigabine has a 
pharmacological profile similar to retigabine but is 20 times less potent.20 The major route of 
excretion in rats and dogs is in feces, with some compound being excreted in urine.21,22,23 In 
humans, retigabine is mainly metabolized by N-glucuronidation and N-acetylation, and is not 
metabolized by cytochrome P450 enzymes.20 Retigabine has low protein binding in all 
species, including humans.20 Both in vivo and in vitro studies suggest that retigabine is 
unlikely to have any important drug-drug interactions with commonly used drugs.24,25,26,27 
6.3. 
Preclinical Safety Studies 
Retigabine caused motor impairment in rodents in the rotarod test, but the doses necessary 
were 12 to 13 times higher than those active in models of epilepsy.28 Neither retigabine nor 
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its N-acetyl metabolite prolonged action potential duration (APD) in cat cardiac myocytes 
and dog Purkinje fibers, and in fact resulted in slight shortening of APD in these test 
systems.29  At concentrations 17-20 times higher than those achieved at therapeutic doses 
in man, retigabine caused a slight prolongation in QT interval in the isolated guinea pig 
heart, as well as a slight reduction in K+ current through human ether-a-go-go related gene 
(hERG) channels.30 However, retigabine did not affect ECG parameters in anesthetized 
dogs or conscious unrestrained dogs given daily doses for 7 days.31 Retigabine may inhibit 
bladder contractions and micturition in rodents due to its ability to hyperpolarize and stabilize 
urinary bladder myocytes through activation of K+ channels.32 
In acute and chronic toxicity studies in rats, CNS related clinical signs including 
hyperkinesia, hypokinesia, disturbed coordination, stilted gait, tremor and convulsions were 
observed.33 In repeat dose toxicity studies in rodents, slight hepatocellular and thyroid 
follicular hypertrophy were observed and were considered to be adaptive.34,35 In repeat-dose 
studies in dogs but not rodents, self-limiting hepatocellular degeneration was observed in 
regions adjacent to the gallbladder.36,37 In rodents but not dogs, distended urinary bladder or 
urinary bladder ectasia was noted with occasional secondary inflammation and ulceration of 
bladder wall.34,35,36,37 
No retigabine-related effects on reproductive function were observed in male or female rats 
in a fertility and general reproductive performance study.  No teratogenic effects of 
retigabine were observed in rats or rabbits.38,39 In a perinatal and postnatal toxicity study in 
rats, the administration of retigabine to mated females did not have significant effect on the 
development of the offspring, but at the highest dose level growth was slowed, early 
mortality increased, and auditory reflex development was retarded in relation to the delay in 
growth.40  In juvenile rats, retigabine reduced food consumption at the maximum tolerated 
dose but did not affect growth, reflex development, motor activity, learning, memory, clinical 
pathology parameters, or reproductive performance.41  
In genetic toxicity studies, the retigabine active substance, used to manufacture finished 
product, tested negative for mutagenicity in the AMES test.  Some exceptions could be 
explained as false weakly positive results due to alterations of the Salmonella tester 
strains.42,43 Retigabine was negative in 2 independent mammalian cell forward gene 
mutation assays in presence and absence of S-9.42  Retigabine did not induce chromosome 
aberrations in cultured human lymphocytes following pulse treatment for 3 or 4 hours in the 
absence and presence of S-9.43  Following continued treatment for 20 or 22 hours in this test 
system, retigabine induced chromosome aberrations, but only in the absence of S-9.  
Retigabine tested negative in genetic toxicity studies relying for metabolism on unbroken 
cells where the required cofactors are present at their natural concentrations as in the in 
vivo micronucleus test in mice and in the in vivo / in vitro unscheduled DNA synthesis (UDS) 
assay in hepatocytes in rats.44, 45, 46, 47, 48 
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6.4. 
Clinical Studies 
In open-label Phase 2 studies in patients with epilepsy, the majority of patients tolerated 
daily doses of up to 1200 mg administered orally in two or three divided doses.  The most 
commonly observed treatment-emergent adverse effects were in the MedDRA system organ 
class of Nervous System Disorders.  In a double-blind parallel group study comparing 
different titration rates (Study 3065A1-214), it has been shown that when the starting dose 
of retigabine is 300 mg/day (100 mg TID), the daily dose can be titrated to 1200 mg over a 
6-week period with only 13% of patients discontinuing due to adverse events.  
In a randomized, double-blind, placebo-controlled, parallel group study comprising 
397 patients with epilepsy (Study 3065A1-205)52, daily doses of 900 mg and 1200 mg 
(administered orally in three divided doses) caused a significant reduction in total partial 
seizure frequency compared with placebo.  While a dose of 600 mg/day resulted in greater 
reduction of seizure frequency than placebo, the difference was not statistically significant.  
The majority of patients tolerated their treatment as prescribed, with a minority discontinuing 
from the study prematurely. The discontinuation rate due to adverse events in 1200 mg 
dose group was about 2.5 times that in placebo group.  This is consistent with tolerability of 
other AEDs.  The commonly observed adverse events were in the MedDRA system organ 
class of Nervous System Disorder and many of these were dose related and were more 
frequent with retigabine compared with placebo.  There were few clinically important 
changes in vital signs, laboratory, or ECG parameters, or physical or neurological 
examinations. 
Patients participating in Study 3065A1-205 were eligible for an open-label extension phase 
(Study 3065A1-212) if they experienced improvement in seizure control, did not experience 
adverse events that would prevent inclusion, and did not violate the double-blind study 
protocol.  Patients who completed the interim (transition) phase of the double-blind portion 
of the study started with 300 mg TID, which could be increased weekly in increments of 
150 mg/day, up to a maximum of 1200 mg daily.  Concomitant AEDs could be adjusted to 
achieve the best efficacy/safety ratio.  Patients who wished to discontinue retigabine during 
this open-label study entered a 3-week tapering period and a 10-day post-study follow-up 
period.  Seizure frequency was recorded daily in a diary maintained by each patient.  The 
efficacy of retigabine was evaluated by comparison of baseline seizure frequency 
(determined upon entry into the double-blind phase) with seizure frequency during 
retigabine therapy in the extension study; this was calculated as a percentage change in 
total partial seizure frequency. 
Of the 279 patients who completed Study 205, 222 enrolled in the open-label extension.  
The majority of these patients were white (213 or 95.9%) with a median age of 36 years.  A 
total of 126 patients were male (56.8%) and 96 (43.2%) were female. The median duration 
of epilepsy at study entry was 20.7 years.  Of these 222 patients, 18 (8%) discontinued 
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within the first 3 months and 41 (18%) discontinued within 6 months. The most common 
cause for discontinuation was lack of efficacy.  The most common daily dosage of retigabine 
was 900 mg (105 patients; 47.3%) and only a minority of the patients titrated the dosage to 
1200 mg (53 patients; 23.9%).  The median treatment duration during open-label extension 
phase was 358 days. 
The median decrease in monthly total partial seizure frequency from baseline was 48.3%, 
which was similar to the results with the two highest retigabine dose groups (300 and 400 
mg TID) in the randomized, double-blind phase.  Patients assigned to the placebo group 
during the double-blind phase showed the largest seizure rate improvement during the 
extension phase. One hundred three patients (46.4%) showed a reduction in monthly total 
partial seizure frequency of 50%. 
6.5. 
Safety and Tolerability  
The safety and tolerability of various dosing regimens of retigabine were examined in 
healthy patients participating in human pharmacology studies and in patients with epilepsy 
in therapeutic trials.53,54 A total of 404 healthy subjects participated in 18 human 
pharmacology studies.  In a multiple dose-finding trial using fixed doses, regimens up to 200 
mg twice a day (BID) were safe and well tolerated and the maximum tolerated dose was 
found to be 250 mg BID.  However, after allowing for titration to the target dose, regimens 
up to 350 mg BID were tolerated without any dose-limiting adverse events (AEs). In general, 
central nervous system (CNS) AEs limited further dose increases.55 
A total of 605 patients with epilepsy have been enrolled in clinical studies for retigabine. 
Retigabine was mostly administered as add-on therapy to various established background 
AEDs and to a minor extent as monotherapy by using various dose-titration regimens.  The 
maximum tolerated dose (MTD) of retigabine when added to standard AEDs was 1200 
mg/day.  Retigabine was administered using BID and TID regimens. The most common AEs 
were CNS-related (e.g., somnolence, dizziness, confusion, speech disorder, vertigo, 
amnesia, thinking abnormal, tremor, incoordination, ataxia, nervousness, paresthesia, 
abnormal gait, diplopia, and abnormal vision) and appeared in a dose-dependent manner.55  
No AEs of retigabine on cardiac safety and in particular cardiac repolarization (QTc interval) 
were detected.  While the AE pattern from human pharmacology and clinical trials is similar, 
it is interesting to note that MTDs in healthy subjects appear to be different from those 
achieved in patients with epilepsy, despite the concomitant medication with standard AEDs 
in the latter group.  
A complete description of preclinical pharmacology, toxicology, PK studies, and clinical 
safety and efficacy studies for retigabine can be found in the Investigator’s Brochure.56 
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6.6. 
Pharmacokinetics 
6.6.1. 
Absorption  
In clinical trials, retigabine was rapidly absorbed within 2 hours after oral administration to 
healthy patients.49 The N-acetylated metabolite of retigabine was also rapidly formed, 
following the parent compound by approximately 2 hours.  Both retigabine and the N-
acetylated metabolite of retigabine were eliminated with a half-life (t1/2) of about 8 hours.  At 
steady state, mean observed maximum concentration (Cmax) and area under the curve 
(AUC) values of the N-acetylated metabolite were within 20% of the corresponding mean 
values of retigabine.  The trough plasma concentrations of retigabine in the afternoon or 
evening were significantly lower than those in the morning, possibly related to slower 
metabolism during sleep.  The pharmacokinetics (PK) of retigabine and the N-acetylated 
metabolite of retigabine were linearly dose proportional for doses from 100 to 350 mg.  
6.6.2. 
Metabolism 
Investigations of metabolism in humans indicate that retigabine is mainly metabolized by N-
glucuronidation and N-acetylation, and is not metabolized by cytochrome P450 enzymes.20 
In vitro studies have shown that the glucuronidation is performed by several uridine 
diphosphate glucuronyltransferase (UGT) isozymes.50 The PK of retigabine and the N-
acetylated metabolite of retigabine in patients with epilepsy are comparable with those in 
healthy subjects.51 
6.6.3. 
Excretion 
The major route of excretion in rats and dogs is in feces, with some compound being 
excreted in urine.21,22,23 In humans, retigabine is mainly metabolized by N-glucuronidation 
and N-acetylation, and is not metabolized by cytochrome P450 enzymes.20 Retigabine has 
low protein binding in all species, including humans.20 Both in vivo and in vitro studies 
suggest that retigabine is unlikely to have any important drug-drug interactions with 
commonly used drugs.24,25,26,27 
7. STUDY OBJECTIVES 
• 
Primary: To evaluate the safety and tolerability of long-term therapy with retigabine 
administered as adjunctive therapy in adult epilepsy patients with partial-onset 
seizures, who completed the double-blind Study VRX-RET-E22-302. 
• 
Secondary: To evaluate efficacy of long-term treatment with retigabine and patient 
quality of life, evaluated through the QOLIE-31-P questionnaire. 
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8. STUDY DESIGN 
This is an open-label extension study of the placebo controlled, double-blind Study VRX-
RET-E22-302. Patients will be treated with 600-1200 mg/day of retigabine as an adjunct 
therapy to their current antiepileptic medications (AEDs) or vagal nerve stimulation as 
established in Study VRX-RET-E22-302. Following completion of the Transition Phase of 
the double-blind study (Study VRX-RET-E22-302), treatment in this open-label extension 
study will be continued until retigabine is approved and commercially available, or until the 
program is discontinued, followed by a 3-week tapering period and a 30 day post-study 
period for collection of adverse events. 
8.1. 
Type of Study 
Phase 3 open-label extension study for therapeutic use. 
8.2. 
Study Population 
Patients entering this study had to have participated in Study VRX-RET-E22-302, i.e. they 
had met eligibility criteria of that study and completed the double-blind phase. 
8.3. 
Number of Study Sites 
This is a multi-center open-label study involving approximately 55-60 study sites in Western, 
Central and Eastern Europe, Australia, Israel, and South Africa. 
8.4. 
Treatment Duration 
Following completion of the Transition Phase of the double-blind study (Study VRX-RET-
E22-302), treatment in this open-label extension study will be continued until retigabine is 
approved and commercially available, or until the program is discontinued, followed by a 3-
week tapering period and a 30 day post-study period for collection of adverse events.   
8.5. 
Patient Inclusion Criteria 
For inclusion in the study, a patient must meet and comply with the following criteria: 
1. Patient has successfully completed the Maintenance and Transition phases of Study 
VRX-RET-E22-302 for the treatment of partial-onset seizures 
2. Patient is expected to benefit from participation in the study in the opinion of the 
Investigator. 
3. Women of childbearing potential and fertile males have to agree to use a medically 
acceptable method of birth control and females had to have a negative serum β-HCG 
pregnancy test at the last visit of the Transition phase of Study VRX-RET-E22-302. A 
woman of childbearing potential is defined as a female who is biologically capable of 
becoming pregnant. A medically acceptable method of birth control includes an 
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intrauterine device in place for at least 3 months, surgical sterilization (e.g. tubal 
ligation), or adequate barrier methods (e.g., diaphragm and foam). An oral contraceptive 
alone is not considered adequate for the purpose of this study. 
4. In the opinion of the Investigator, patient is able to understand verbal and written 
instructions and will adhere to all study schedules and requirements. 
5. Patient or legal guardian (if applicable) is informed, given ample time and opportunity to 
read and/or understand about his/her participation in the study, and has signed and 
dated the written informed consent form. 
8.6. 
Patient Exclusion Criteria 
A patient is ineligible for entering Study VRX-RET-E22-304 if any of the following exclusion 
criteria are met: 
1. Patient meets any of the withdrawal criteria in the previous VRX-RET-E22-302 study or 
is experiencing an ongoing serious adverse event. 
2. Patient is receiving any investigational drug or using any experimental device in addition 
to Retigabine for treatment of epilepsy or any other medical condition. 
3. Patient has any other condition that would prevent compliance with the study procedures 
or proper reporting of AEs. 
8.7. 
Study Medication 
Study medication will be supplied by Valeant Research & Development, as film-coated 
tablets containing 50 mg, 100 mg, or 300 mg of retigabine per tablet. Tablets will be 
packaged in induction sealed bottles.  A sufficient supply of study medication will be 
provided to each site for completion of the trial, based on the number of patients enrolled, 
study visit schedule, and the daily doses of patients. Specific dosage instructions will be 
provided separately to the patient. All study medication will be dispensed by the pharmacy 
or an appropriately qualified member of the study staff assigned by the Principal Investigator 
to this task. 
Patients will take the established background AEDs from their own prescriptions, and their 
use will be recorded. 
8.7.1. 
Dosage Schedule and Mode of Administration 
Patients who completed the Transition phase of Study VRX-RET-E22-302 will start with 300 
mg three times a day (300 mg TID).  Patients who were not able to tolerate the final dose 
adjustment (750 mg/day) during the last week of the Transition phase of Study VRX-RET-
E22-302 will start with 200 mg three times a day (200 mg TID).  
If, in the opinion of the Investigator, the patient was not receiving the maximum effective 
dose, the dose could be increased in weekly intervals of 150 mg/day, up to a maximum of 
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1200 mg daily (i.e. 400 mg TID). If adverse events considered to be secondary to retigabine 
occur, the total daily dose could be reduced by 150 mg/day every week, at Investigator 
discretion, as long as the dose is within 600-1200 mg/day. 
After the patient has entered open-label treatment, the Investigator may add new AEDs, as 
long as these are approved AEDs. In addition, the existing background AED therapy can be 
adjusted to achieve the best efficacy/safety ratio, as needed, per Investigator discretion. If 
necessary, in the Investigator’s judgment, all background AEDs can be discontinued to 
achieve monotherapy with retigabine. 
Patients who permanently discontinue open-label treatment will have their dose tapered by 
one-third every week. 
Patients will be instructed on the administration procedures for study drug. Study medication 
will be administered orally with or without food. The 3 daily doses are to be administered 
with approximately an 8-hour interval between them (for example 7am, 3pm, 11pm). 
Patients will continue to take their established background AEDs from their own 
prescriptions. 
8.7.2. 
Study Drug Storage 
All study drug sent to the study centers must be stored under the conditions specified on the 
drug package label (15 – 30 °C / 59 – 86 °F) in a secure area accessible only to the 
Investigator and his/her designated staff.  All study drugs should be stored and inventoried 
according to applicable government regulations and study procedures. 
8.7.3. 
Study Drug Returns 
Government regulations require that all investigational drug materials not used in clinical 
trials be returned before or at the completion of the study. 
The Investigator will return the designated copies of the completed dispensing and inventory 
record. 
8.7.4. 
Method of Assigning Study Medication to Patients 
Study medication will be assigned to patients through a centralized Interactive Voice 
Response System (IVRS), as described in the IVRS user manual that will be provided to the 
sites.  Sites will contact the IVRS to obtain the package number assignment(s) for patients 
at each scheduled study visit 
Study personnel will select the study medication bottle(s) from their inventory that 
correspond to the package number(s) assigned by IVRS. Study personnel will complete the 
tear-off labels on the bottles, affix them to the Investigational Product Labels page found in 
the patient’s paper source binder, and dispense the study medication (bottles) to the patient.  
At subsequent study visits, study personnel will follow the same procedures as described 
above, contacting the IVRS as instructed in the IVRS manual. 
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8.7.5. 
Discontinuation and Tapering of Study Medication 
Patients who discontinue early from the open-label extension study will have their study 
medication tapered over a 3-week period, reducing their daily dose by one-third per week. 
After tapering has been completed, patients should return to the site immediately, and 
complete all assessments and evaluations scheduled for Visit 5, if patient discontinued early 
during the first year of the open-label extension study, complete all assessments and 
evaluations scheduled for Visit 8 if patient discontinued early during the second year of the 
open-label extension study, and complete all assessments and evaluations scheduled for 
Visit 11 if patient discontinued early during the third year of the open-label extension study 
(Refer to Study Flow Chart in Appendix A). 
8.8. 
Assessment of Compliance 
Patient compliance with the study drug dosing regimen will be assessed by counts of tablets 
remaining in the study medication bottles that are returned at each study visit.  Compliance 
will be based on the medication the patient was scheduled to take for the days between 
study visits.  In addition, information on the average total daily dose will be calculated, based 
on the number of tablets remaining or returned in each bottle. 
Patients will be instructed to bring used and unused study medication bottles with them to 
each study visit for accountability purposes. Tablets from each bottle for each dose strength 
(50 mg, 100 mg, 300 mg) will be counted and recorded to assess patient compliance and 
correct dosage taken.  If a patient is deemed to be non-compliant with taking study 
medication, the patient should be counseled by the site.  If the patient continues to be non-
compliant, they should be withdrawn from the study. 
Along with drug accountability logs, the CRF will capture the data which includes the 
prescribed dosage, dates of first dose and last dose, and the number of tablets returned 
from each bottle for each dose strength. The CRFs will also provide a classification in to 
poly- or monotherapy with retigabine. 
8.9. 
Concomitant Therapy 
8.9.1. 
Permitted Concomitant Medications 
Patients will take the background AED as prescribed by their physician. If adverse events 
considered to be secondary to retigabine occur, the total daily dose could be reduced by 
150 mg/day every week, at Investigator discretion, as long as the dose is within 600-1200 
mg/day.  The background AED therapy can be adjusted if a patient develops adverse events 
similar to the previously experienced reaction to that AED.   
After patients enter the open-label extension study, the Investigator will be allowed to adjust 
background AEDs, as clinically indicated.  As needed, the background AED therapy can be 
adjusted to achieve the best efficacy/safety ratio, per Investigator discretion.  If necessary, in 
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the Investigator judgment, all background AEDs can be discontinued to achieve 
monotherapy with retigabine.  The dose and reason to use a concomitant medication shall 
be recorded in the CRFs. 
8.9.2. 
Prohibited Medications 
Use of felbamate and vigabatrin are prohibited. Concurrent use of any AEDs, or of any drug 
that could interfere with the absorption or metabolism of retigabine and background AED is 
also prohibited.  Medications known to lower seizures (e.g. neuroleptics) and monoamine 
oxidase inhibitors (MAOIs) are not allowed. 
8.10. Protocol Violations and Deviations 
A deviation from the protocol is an unintended and/or unanticipated departure from the 
procedures and/or processes approved by the Sponsor and the IRB/IEC/REB and agreed to 
by the Investigator. Deviations usually have an impact on individual patients or a small 
group of patients. A protocol violation occurs when there is non-adherence to the protocol 
that results in a significant, additional risk to the patient, when the patient or Investigator has 
failed to adhere to critical protocol requirements (inclusion/exclusion criteria) and the patient 
was enrolled without prior Sponsor approval, or when there is non-adherence to FDA 
regulations and/or ICH GCP guidelines. 
The Investigator or designee must document and explain any deviation or violation from the 
approved protocol. The Investigator may implement a deviation from, or a change of the 
protocol to eliminate an immediate hazard to study patients without prior IRB/IEC/REB 
approval. Immediately after the implemented deviation, violation or change to eliminate the 
immediate hazard to the study patient(s), the Investigator must submit a report explaining 
the reasons for the protocol deviation, violation or change to the Sponsor. If required, the 
regulatory authorities will be notified. The appropriate IRB/IEC/REB will be notified of 
specified, critical violations or violations that place patients at added, significant risk. 
Protocol violations and deviations will be documented by the clinical monitor throughout the 
course of the monitoring visits. Investigators will be notified of violations and deviations 
and/or in writing by the monitor, and the Principal Investigator will be required to identify 
corrective action to eliminate future violations and deviations. 
9. STUDY PROCEDURES 
9.1. 
Study Flow Chart 
As presented in the Study Flow Chart (see Appendix A), Study Visit 1 will have a window 
range of ±3 days.  After Study Visit 1, all remaining study visits will have a window range of 
±7 days around that visit day to accommodate individual schedules, as follows: 
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• 
Baseline for the open-label extension study corresponds to the assessments 
performed at the last visit of the Maintenance phase (Visit 9) of Study VRX-RET-E22-302 for 
all patients.  The final, baseline eligibility assessment for the open-label extension study, 
including obtaining informed consent and dispensing open-label study medication will be 
performed at the last visit of the Transition phase (Visit 11) of Study VRX-RET-E22-302. 
• 
Study Visit 1 (at Month 1 ±3 days). 
• 
Study Visit 2 (at Month 3 ±7 days). 
• 
Study Visit 3 (at Month 6 ±7 days). 
• 
Study Visit 4 (at Month 9 ±7 days). 
• 
Study Visit 5 (at Month 12 ±7 days). 
• 
Study Visit 6 (at Month 16 ±7 days). 
• 
Study Visit 7 (at Month 20 ±7 days). 
• 
Study Visit 8 (at Month 24 ±7 days). 
• 
Study Visit 9 (at Month 28 ±7 days). 
• 
Study Visit 10 (at Month 32 ±7 days). 
• 
Study Visit 11 (at Month 36 ±7 days). 
Each study month will be defined as 30 calendar days.  If a patient visit occurs outside the 
visit window, the study clinical monitor (CRA) should be notified and the reason for the 
deviation noted. An attempt should be made to ensure that the patient returns for 
subsequent visits on schedule using the last visit of the Transition phase (Visit 11) of Study 
VRX-RET-E22-302, which corresponds to the final, baseline eligibility visit for the open-label 
extension study. 
9.2. 
Efficacy Assessments 
Patients will keep a seizure diary throughout the study. The anticonvulsant efficacy of 
retigabine will be evaluated by comparison of baseline seizure frequency (obtained during 
the 8-week baseline period of Study VRX-RET-E22-302) with seizure frequency obtained 
during retigabine therapy in this open-label extension study (VRX-RET-E22-304). The 
primary efficacy variable is the percentage change in the monthly seizure rate from the 
baseline phase to the open-label treatment phase. The proportion of responders (patients 
experiencing ≥ 50% reduction in seizure frequency) from baseline to the open-label 
treatment phase will also be evaluated. 
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9.3. 
Safety Assessments 
Safety assessments will be evaluated, based on reports of AEs and results of vital signs 
(supine and standing blood pressure, pulse, and temperature), weight, clinical laboratory 
evaluations (blood chemistries, hematology and urinalysis including microscopy), a 12-lead 
ECG, and physical and neurological examinations. Post-void residual (PVR) bladder 
ultrasounds to assess urinary retention and the American Urological Association (AUA) 
Symptom Index to assess urinary voiding function will also be performed during the first year 
of the open-label extension study. 
9.3.1. 
Vital Sign Measurements and Weight 
Complete vital sign measurements (including supine and standing blood pressure, heart 
rate, and temperature) will be obtained throughout the study at all visits. Evaluations of 
blood pressure and heart rate will be performed supine at each study visit, and again after 
the patient has been standing for approximately 2 minutes.  
Weight [pounds (lb) or kilograms (kg)] will also be measured in ordinary indoor clothing 
(without shoes) and will be recorded at all study visits  
Abnormal vital sign values that are deemed clinically significant by the Investigator will be 
reported as AEs in the study CRF. 
9.3.2. 
Physical and Neurological Examinations 
A complete physical and neurological examination will be performed annually at Visit 5, Visit 
8, and Visit 11.  Brief neurological examinations will be performed at all other study visits, 
including visits 1, 2, 3, 4, 6, 7, 9, and 10. 
9.3.3. 
Electrocardiograms 
A 12-lead ECG will be performed at all study visits during the first year of the open-label 
extension study (Visits 1, 2, 3, 4, 5), and annually at Visits 8 and 11. The ECG parameters 
that will be assessed are heart rate, PR interval, QRS interval, QT interval, and QTc interval.  
All ECG tracings will be sent to Quintiles ECG Services for central reading.  Quintiles ECG 
Services will provide a central ECG analysis and transmit a feedback of preliminary results 
via facsimile to the investigation site within 24 hours.  Trained technicians will read all ECGs 
manually, and any abnormal finding will then be over-read by board-certified cardiologists.  
QT intervals will be corrected using both Bazett’s and Fridericia’s formulas.  For purposes of 
clinical study conduct, Bazett’s QT correction will be used.  For purposes of data analysis, 
Fridericia’s QT correction will be considered as primary.  Changes from baseline QTc 
interval will be monitored on an ongoing basis throughout this study.   
Increases in Bazett’s QTc interval of >60 msec from baseline or QTc interval of >500 msec 
anytime during the study should be confirmed on a repeat ECG.  Any such occurrence shall 
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result in notification of the Investigator and the study medical monitor for immediate review 
of the tracings and discussion with Valeant. 
9.3.4. 
Laboratory Assessments 
All clinical laboratory assessments will be performed by a central laboratory (Quintiles 
Central Laboratory Services), which will provide instructions and supplies to the study staff 
before study initiation.  Results of the clinical laboratory assessments will be faxed back to 
the study site within 48 to 72 hours of sampling.  Alert values will be reported to the 
Investigator via telephone.  Approximately 7-mL sample of blood will be drawn for clinical 
chemistries and hematology assays.  The laboratory assessments will include routine 
laboratory tests.  The clinical laboratory evaluation will be performed at all study visits during 
the open-label extension study. 
Because of the bladder toxicity observed in chronic toxicology studies in the rat and mouse, 
careful attention will be paid to plasma creatinine and blood urea nitrogen (BUN), 
microscopic findings on urinalysis, and any symptoms that might suggest incomplete 
bladder emptying (e.g., urinary tract infection, frequency, sensation of incomplete voiding, 
etc.).  All patients will undergo urinalysis (including microscopy) at all study visits. 
Any patient who has developed a clinically significant urinalysis abnormality will undergo 
further evaluation by an urologist (as clinically indicated) for any of the following: 
• 
>5 red blood cells (RBC) per high power field (HPF) for males and postmenopausal 
females or >8 RBC/HPF for females 
• 
>3 white blood cells(WBC) per high power field (HFP) for males and >12 WBC/HPF 
for females 
• 
>1+ epithelial cells 
• 
≥1+ on all casts except Hyaline casts ≥2+ 
• 
>1+ blood for males and postmenopausal females 
• 
≥1+ trace protein [RBC; males and postmenopausal females] per high power field 
(HPF) or >5 white blood cells [WBC; must have 1 to few epithelial cells/HPF] per 
HPF, >occasional casts, >1+ blood [male and postmenopausal female patients] or 
>trace protein 
• 
Have symptoms or AEs suggestive of possible hypotonicity of the bladder 
The laboratory evaluations will include: 
1. Hematology: hemoglobin, hematocrit, RBC count, WBC count with differential, and 
platelet count. 
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2. Blood chemistries: sodium, potassium, chloride, bicarbonate, glucose, cholesterol, 
creatinine, calcium, phosphorus, BUN, uric acid, total bilirubin, total protein, AST, ALT, 
and alkaline phosphatase levels.  
3. Pregnancy tests: a serum β-HCG pregnancy test for women of childbearing potential 
will be performed at Study Visit 5 and annually thereafter.  In addition to the scheduled 
pregnancy tests, a pregnancy test should be performed during the study whenever a 
woman’s menstrual period is 5 days late. 
4. Routine urinalysis: specific gravity, pH, protein/albumin, glucose/sugar, 
ketones/acetone, and hemoglobin/blood.  In order to standardize measurements, Bayer 
multistix 8-SG or equivalent dipsticks will be used.  
5. Microscopic urinalysis: RBC, WBC, casts, and crystals/cells. 
All laboratory tests with values that become abnormal after drug administration will be 
repeated as clinically indicated until the values return to normal, or until the etiology has 
been determined and the condition considered stable. Abnormal laboratory test results that 
are considered to be clinically important by the Investigator will be reported as an AE in the 
CRF.  A laboratory abnormality will not be considered an AE unless: 
• 
Intervention is required. 
• 
Changes in dose of retigabine are required (decrease, discontinued, interrupted). 
• 
Other treatment/therapy is required. 
• 
Associated with other diagnoses. 
Laboratory results will be reported to the Investigator who will review abnormal laboratory 
findings for clinical significance.  The Investigator will note any laboratory test results of 
clinical concern, or values that were outside normal ranges and provide details of the 
relationship to study drug and the action taken.  If a change in a laboratory value represents 
a medical condition, the medical condition will be listed in the AE record. If no correlation is 
possible, the direction of change (increase or decrease) rather than the actual value will be 
recorded. 
9.3.5. 
Post-Void Residual (PVR) Bladder Ultrasound 
A post-void residual (PVR) bladder ultrasound to assess urinary retention will be performed 
at Visits 1, 2, and 5, during the first year of the open-label extension study. 
9.3.6. 
AUA Symptom Index 
An AUA Symptom Index, a 7-item Likert-scored scale describing urinary bladder function, 
will be completed by the Investigator at Visits 1, 2, and 5, during the first year of the open-
label extension study, to assess the patient’s urinary voiding function. The AUA Symptom 
Index is included in Appendix D of this protocol. 
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9.4. 
Quality of Life Assessments 
The QOLIE-31-P (Version 2.0) will be utilized to assess quality of life. The QOLIE-31-P 
assessment must be completed by the patients.  Patients who are cognitively impaired and 
cannot complete the QOLIE-31-P assessment may still participate in the study, by obtaining 
a waiver for QOLIE-31-P completion from the study medical monitor. 
9.5. 
Baseline 
Except for final study eligibility, informed consent and dispensation of open-label extension 
study medication, the Baseline assessments for the open-label extension study correspond 
to the assessments performed at the last visit of the Maintenance phase (Visit 9) of Study 
VRX-RET-E22-302 (See Study Flow Diagram - Appendix A).  After completion of all study 
procedures on the last visit of the Transition phase (Visit 11) of Study VRX-RET-E22-302, 
patients will be allowed to enter this open-label extension study (VRX-RET-E22-304).  All 
ongoing AEs and concomitant medications at the last visit of the Transition Phase (Visit 11) 
of Study VRX-RET-E22-302 will need to be transferred and captured on the appropriate 
open-label extension AE and Concomitant Medication CRF pages.  The final study eligibility 
and informed consent for the open-label extension study will be performed at the last visit of 
the Transition phase (Visit 11) of Study VRX-RET-E22-302. After confirmation of final study 
eligibility and obtaining proper informed consent, open-label study medication (sufficient 
supply of bottles at appropriate dose strengths = 50 mg, 100 mg, 300 mg) will be dispensed 
to patients, along with seizure diaries for completion until the next study visit (Visit 1 / Month 
1).  
9.6. 
Study Visit 1 (Month 1) 
Patients will return for Study Visit 1 (Month 1). At this visit, the following evaluations will be 
performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Brief Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
12-lead ECG 
• 
AUA Symptom Index 
• 
PVR Bladder Ultrasound 
• 
Adverse Events 
• 
Concomitant Medication 
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• 
Open-Label Study Medication (collect returned medication and dispense new 
medication) 
9.7. 
Study Visit 2 (Month 3) 
Patients will return for Study Visit 2 (Month 3). At this visit, the following evaluations will be 
performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Brief Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
12-lead ECG 
• 
AUA Symptom Index 
• 
PVR Bladder Ultrasound 
• 
Adverse Events 
• 
Concomitant Medication 
• 
QOLIE-31-P Questionnaire (completed by patient) 
• 
Open-Label Study Medication (collect returned medication and dispense new 
medication) 
9.8. 
Study Visit 3 (Month 6) 
Patients will return for Study Visit 3 (Month 6). At this visit, the following evaluations will be 
performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Brief Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
12-lead ECG 
• 
Adverse Events 
• 
Concomitant Medication 
• 
QOLIE-31-P Questionnaire (completed by patient) 
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• 
Open-Label Study Medication (collect returned medication and dispense new 
medication) 
9.9. 
Study Visit 4 (Month 9) 
Patients will return for Study Visit 4 (Month 9). At this visit, the following evaluations will be 
performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Brief Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
12-lead ECG 
• 
Adverse Events 
• 
Concomitant Medication 
• 
QOLIE-31-P Questionnaire (completed by patient) 
• 
Open-Label Study Medication (collect returned medication and dispense new 
medication) 
9.10. Study Visit 5 (Month 12) 
Patients will return for Study Visit 5 (Month 12). At this visit, the following evaluations will be 
performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Complete Physical and Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
Serum Pregnancy Test 
• 
12-lead ECG 
• 
AUA Symptom Index 
• 
PVR Bladder Ultrasound 
• 
Adverse Events 
• 
Concomitant Medication 
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• 
QOLIE-31-P Questionnaire (completed by patient) 
• 
Open-Label Study Medication (collect returned medication and dispense new 
medication) 
9.11. Study Visits after the First Year 
After the first year of open-label extension study, the study visits will occur every 4 months 
(3 visits per year), and will continue until retigabine is approved and commercially available, 
or until the program is discontinued.  The assessments for the first 2 study visits of each 
year will be identical, and the assessments for the last study visit of each year will be 
identical.  To provide guidance, the following study visits and assessments will be performed 
during the second and third years of the open-label extension study: 
9.11.1. 
Visit 6 (Month 16) 
Patients will return for Study Visit 6 (Month 16), 4 months after Visit 5.  At this visit, the 
following evaluations will be performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Brief Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
Adverse Events 
• 
Concomitant Medication 
• 
Open-Label Study Medication (Collect returned medication and dispense new 
medication) 
9.11.2. 
Visit 7 (Month 20) 
Patients will return for Study Visit 7 (Month 20).  At this visit, the following evaluations will be 
performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Brief Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
Adverse Events 
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• 
Concomitant Medication 
• 
Open-Label Study Medication (Collect returned medication and dispense new 
medication) 
9.11.3. 
Visit 8 (Month 24) 
Patients will return for Study Visit 8 (Month 24).  At this visit, the following evaluations will be 
performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Complete Physical and Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
Serum Pregnancy Test 
• 
12-lead ECG 
• 
Adverse Events 
• 
Concomitant Medication 
• 
QOLIE-31-P Questionnaire (completed by patient) 
• 
Open-Label Study Medication (collect returned medication and dispense new 
medication) 
9.11.4. 
Visit 9 (Month 28) 
Patients will return for Study Visit 9 (Month 28).  At this visit, the following evaluations will be 
performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Brief Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
Adverse Events 
• 
Concomitant Medication 
• 
Open-Label Study Medication (Collect returned medication and dispense new 
medication) 
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9.11.5. 
Visit 10 (Month 32) 
Patients will return for Study Visit 10 (Month 32).  At this visit, the following evaluations will 
be performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Brief Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
Adverse Events 
• 
Concomitant Medication 
• 
Open-Label Study Medication (Collect returned medication and dispense new 
medication) 
9.11.6. 
Visit 11 (Month 36) 
Patients will return for Study Visit 11 (Month 36).  At this visit, the following evaluations will 
be performed: 
• 
Seizure Diary (collection / review of current diary and dispensation of new diary) 
• 
Complete Physical and Neurological Exam 
• 
Vital Signs (BP, HR, and Temperature) and Body Weight 
• 
Clinical Laboratory Tests (Blood Chemistries, Hematology, Urinalysis including 
microscopy) 
• 
Serum Pregnancy Test 
• 
12-lead ECG 
• 
Adverse Events 
• 
Concomitant Medication 
• 
QOLIE-31-P Questionnaire (completed by patient) 
• 
Open-Label Study Medication (collect returned medication and dispense new 
medication) 
9.12. Tapering Period 
All patients who discontinue early from study treatment during the open-label extension 
study will have their study medication tapered over a 3-week period, reducing their daily 
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dose by one-third per week, and return immediately for a final visit. The patients will be 
instructed to take the tablets from their existing study medication bottles and to follow this 
tapering procedure: 
• 
During the first week of tapering, patients will no longer take the afternoon dose. 
• 
During the second week of tapering, patients will no longer take the morning and the 
afternoon doses. 
• 
During the third week of tapering, patients will take no study medication (but will 
continue their existing background AEDs).   
During the first year, these patients should then return for a final visit to complete all 
assessments and evaluations scheduled for Study Visit 5. During the second year, these 
patients should then return for a final visit to complete all assessments and evaluations 
scheduled for Study Visit 8. During the third year, these patients should then return for a 
final visit to complete all assessments and evaluations scheduled for Study Visit 11 (Refer to 
Study Flow Chart in Appendix A).  
During the tapering period, a new background AED should not be added until after the 
patient’s final visit unless clinically necessary for patient safety. Unused current study 
medication bottles will be collected to ascertain compliance. Current study seizure diaries 
will be collected and reviewed. Concomitant medications and AED usage will be 
documented, and adverse events will be recorded.  
9.13. Replacement of Patients 
Patients withdrawn from the study will not be replaced. 
9.14. Unscheduled Visits 
Unscheduled visits may be performed if required for assessments of laboratory parameters 
or clinical safety. 
9.15. Laboratory Procedures 
All clinical safety laboratory determinations will be performed by Quintiles Central Laboratory 
Services. The study staff will send the samples to the appropriate address (provided in the 
Central Laboratory Manual) by shipping them in the laboratory kits supplied by Quintiles 
Central Laboratory. Central laboratory reports will be sent to the Investigator for evaluation.  
An Investigator may choose to use a local laboratory to evaluate a potential adverse event. 
However, for the purpose of this study, data from local laboratories will not be recorded or 
used in the analysis of safety. The Sponsor will not cover costs associated with the use of a 
local laboratory. 
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9.16. Early Termination / Withdrawal Visits 
The Principal Investigator may discontinue a patient from the study for any of the following 
reasons: the patient no longer meets eligibility criteria, it is in the patient’s best interest, 
patient preference, concurrent illness, noncompliance, etc. Patients will be informed prior to 
study entry that they are free to withdraw from the study at any time and for any reason. If a 
patient is discontinued from the study, the Investigator will immediately notify the Sponsor or 
the site CRA of the withdrawal. 
Patients who withdraw from the study prior to completion for any reason (adverse event, 
withdrew consent, etc.) will have their study medication tapered over a 3-week period, 
reducing their daily dose by one-third per week and then return for a final visit.  Patients who 
discontinue early during the first year of the open-label extension study will complete all 
assessments and evaluations scheduled for Study Visit 5.  Patients who discontinue early 
during the second year of the open-label extension study will complete all assessments and 
evaluations scheduled for Study Visit 8.  Patients who discontinue early during the third year 
of the open-label extension study will complete all assessments and evaluations scheduled 
for Study Visit 11 (Refer to Study Flow Chart in Appendix A). 
9.16.1. 
Reasons for Withdrawal 
Patients are free to discontinue their participation in the study at any time and without 
prejudice to further treatment at their local site. The Investigator must withdraw any patient 
from the study if that patient requests to be withdrawn.   
Patients withdrawn from the study will not be replaced, regardless of the reason for 
withdrawal. The patient’s participation in this study may be discontinued due to the following 
reasons: 
• 
Patient experiences an intolerable AE. 
• 
Investigator decides patient has an “unsatisfactory response – efficacy.” 
• 
Patient becomes pregnant. 
• 
Patient is unwilling or unable to continue the study. 
• 
Patient is non-compliant with study procedures. 
• 
Patient needs medication not allowed in the protocol. 
• 
Any clinically significant change in patient’s medical condition. 
• 
Persistent ALT or aspartate aminotransferase (AST) above 3 times the ULN; will be 
confirmed by repeating laboratory assessment within 1 week. 
• 
ALT or AST levels are above 5 times the ULN at any time during the study. 
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• 
Confirmed QTc prolongation defined as QTc (Bazett’s) >500 msec or an increase in 
QTc (Bazett’s) of >60 msec from baseline. 
• 
Investigator decides that withdrawal from the study is in the best interest of the 
patient. 
• 
Request of the Sponsor. 
9.16.2. 
Handling of Withdrawals 
If a patient is withdrawn from the study either at the patient’s request or at the Investigator’s 
decision or the patient fails to return, every effort should be made to determine the reason.  
This information will be recorded on the patient’s case report form (CRF) and recorded by 
IVRS.  
All patients who withdraw from the study prematurely, regardless of cause, should have their 
study medication tapered over a 3-week period, reducing their daily dose by one-third per 
week, and follow the tapering procedures outlined in Section 9.12 (Tapering Period). 
It is important to obtain follow up data for any patient withdrawn because of an AE, abnormal 
laboratory test, or ECG finding.  In any case, every effort must be made to undertake safety 
follow up procedures. 
10. STATISTICAL MEASUREMENTS, EVALUATIONS AND 
ANALYTICAL METHODS 
10.1. Assessment of Efficacy 
Monthly total seizure rates will be calculated for the entire open-label part of Study VRX-
RET-E22-304 and described statistically. Monthly total seizure rates observed during the 
open-label extension period will be compared to the monthly total seizure rates observed 
during the Baseline phase of the double-blind study VRX-RET-E22-302. The percent 
change in monthly total seizure rates from the Baseline phase will be classified into <0, [0, 
25), [25, 50), [50, 75), [75, 100] and described. The responder rate during the open-label 
study (defined as a reduction in seizure frequency ≥50%) will also be summarized using 
descriptive statistics.  
The number of seizure free days, in percent to the individual duration of the open-label 
treatment, will be calculated and summarized using descriptive statistics. This percentage 
will be classified into [0, 25), [25, 50), [50, 75), [75, 95), [95,100), [=100] and described 
statistically.  
All-cause withdrawal rates will be calculated as a percentage and respective "times to event" 
will be described by a Kaplan-Meier survival curve. Specific reasons for withdrawal will also 
be described separately. 
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Besides the categorical analysis mentioned above, the continuous efficacy measurements 
(such as percent change in monthly total seizure rate from the baseline, etc.) will be 
analyzed by analysis of covariance (ANCOVA) with treatment and center as fixed factors 
and the baseline value of the efficacy measurement as covariate. Rank analysis of 
covariance will be used if necessary; however adjusted means will not be presented 
because the data are ranked. The responder rates will be analyzed to check the consistency 
of treatment response in double-blind and open label extension studies. The complete 
details of efficacy analyses will be described in the Statistical Analysis Plan. 
10.2. Assessment of Safety 
Adverse events (AEs) will be monitored from the start of this extension study (informed 
consent provided by patient at the Baseline visit) until 30 days after administration of the last 
dose of study drug (end of study drug taper-off). Treatment-emergent adverse events 
(TEAEs) will be summarized with respect to overall incidence, as well as severity and 
relationship of the AEs to the study drugs.  AEs that result in dose modification, 
discontinuation of the study drug, or serious adverse events will also be summarized  
AEs with onset after the initiation of study drug and within 30 days after the last dose of 
study drug may be considered treatment-emergent. This will include any AE with onset prior 
to initiation of study drug that increased in severity during the treatment period. All reported 
AEs including those with onset more than 30 days after the last dose of study drug will be 
included in the data listings. 
Abnormal changes in laboratory parameters that are not disease-related will be monitored 
and recorded throughout the study.  
All adverse events will be encoded according to MedDRA 8.0.  Treatment emergent adverse 
events (TEAE) will be analyzed, i.e. all adverse events starting or worsening between start 
of long-term extension study up to 30 days after end of study drug taper-off. Incidences on 
preferred term and body system basis will be calculated for all TEAEs. 
Different categories for causality will be recorded in the CRFs, and these 4 categories 
(DEFINITE, PROBABLE, POSSIBLE, and NOT RELATED) are defined in Section 11.3 
(Criteria for Determining Relationship to Study Drug) of this protocol. 
In addition, all SAEs and all AEs leading to premature discontinuation will be presented as 
separate listings. TEAE from both studies (double-blind and open-label extension) will be 
combined, i.e. each patient will be counted just once (with patient’s respective TEAE). 
Other safety evaluations, such as vital signs, physical and neurological examinations, 
laboratory variables, ECG variables, post-void residual bladder ultrasound, and AUA 
symptom index will be analyzed descriptively. 
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Besides descriptive statistics of the safety evaluations will be presented, the incidence of 
TEAEs will be compared across treatment group using Fisher’s Exact test, only for those 
events with an incidence of ≥ 5% over all treatment groups.  Fisher’s Exact test will be 
applied if necessary for other safety evaluations (vital signs, physical and neurological 
examinations, laboratory variables, etc.). QTc interval prolongations will be examined by 
using both Bazett’s and Fridericia’s QT correction formulas. The complete details of safety 
analyses will be described in the Statistical Analysis Plan. 
10.3. Determination of Sample Size 
Not applicable for this long-term extension study. 
10.4. Additional Statistical Considerations 
10.4.1. 
Analysis Population 
The safety population will include all patients who successfully complete the Transition 
phase of Study VRX-RET-E22-302 and were included in this long-term study. The Transition 
phase is the phase of Study VRX-RET-E22-302 during which patients were adjusted to a 
300 mg TID dose. No other population for analysis is defined for this long-term extension. 
10.4.2. 
Handling of Missing Data 
No imputation will be made for missing data in the safety analyses, with the exception of 
incomplete date variables regarding adverse events onset date that is necessary for defining 
treatment-emergent adverse events. More details on imputation of partial dates will be 
provided in the statistical analysis plan.  
11. ADVERSE EVENTS 
An adverse event (AE) is defined as any untoward clinical occurrence in a patient 
administered a pharmaceutical drug product that does not necessarily have a causal 
relationship with the study drug. An AE can therefore be any unfavorable and unintended 
sign (including an abnormal laboratory finding), symptom or disease temporarily associated 
with the use of a drug product, whether or not related to the drug product.  
The presence or occurrence of any of those clinical manifestations and/or alterations in 
clinical laboratory test results that are either present before participation in this study or that 
are part of the normal fluctuations or progression of their pre-study health state, will not 
engender an AE report to the health authorities. Clinical manifestations and/or abnormal 
laboratory values measured during the study that are a sign of worsening of the patient’s 
pre-study health status or that are new findings may, if clinically relevant, be an AE 
reportable to the health authorities. Abnormal laboratory values represent adverse events 
when they are indicative of a disease or defect (e.g., reduced hematocrit resulting in 
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anemia), necessitate intervention (e.g., administration of packed red blood cells or other 
therapies), or result in dose reduction or permanent discontinuation of the drug product. 
Throughout the course of the study, AEs will be monitored and recorded on the patients’ 
source documents and CRFs. The onset, seriousness, intensity, duration, actions taken, 
effect on study drug administration (e.g., discontinuation), the potential relationship to the 
study drug, as well as the date of resolution, if any, will be recorded. 
11.1. Definition and Grading Intensity 
Serious Adverse Events 
A serious adverse event (SAE) is an event that results in any of the following outcomes: 
• 
Death. 
• 
Life-threatening adverse experience. 
• 
Hospitalization (unplanned hospital stay) or prolongation of existing hospitalization. 
• 
Persistent or significant disability/incapacity. 
• 
Congenital anomaly/birth defect. 
Important medical events that may not result in death, be life-threatening or require 
hospitalization may be considered serious adverse events when, based on appropriate 
medical judgment, they may jeopardize the subject and may require medical or surgical 
intervention to prevent one of the outcomes listed above. 
Planned hospitalization or surgery for a condition present prior to the participant’s enrollment 
in the study will not meet the definition of an SAE. 
11.2. Intensity 
The relationship to the study drug and the intensity of an AE should be assessed by the 
Investigator using the following guidelines: 
MILD 
= 
Causing no limitation of usual activities; the patient may experience 
slight discomfort. 
MODERATE 
= 
Causing some limitation of usual activities; the patient may 
experience annoying discomfort; may warrant intervention. 
SEVERE 
= 
Causing inability to carry out usual activities; the patient may 
experience intolerable discomfort or pain; warrants intervention. 
11.3. Criteria for Determining Relationship to Drug 
The Investigator should assess the relationship of the adverse event to the study drug 
according to the following guidelines: 
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DEFINITE 
= 
An event that follows a reasonable temporal sequence from 
administration of the drug or in which the drug level has been 
established in body fluids or tissue; that follows a known or expected 
response pattern to the suspected drug; and that is confirmed by 
improvement on stopping or reducing the dosage of the drug, and 
reappearance of the reaction on repeated exposure. 
PROBABLE 
= 
An event that follows a reasonable temporal sequence from 
administration of the drug; that follows a known or expected 
response pattern to the suspected drug; that is confirmed by 
stopping or reducing the dosage of the drug; and that could not be 
reasonably explained by the known characteristics of the patient’s 
clinical state. 
POSSIBLE 
= 
An event that follows a reasonable temporal sequence from 
administration of the drug; that follows a known or expected 
response pattern to the suspected drug; but that could readily be 
produced by a number of other factors. 
NOT RELATED = 
Any event that does not meet the above criteria. 
11.4. Reporting of Adverse Events 
All AEs should be recorded on the appropriate CRFs. All SAEs, whether or not deemed 
drug-related or expected, must be recorded on the CRFs and SAE forms and reported by 
the Investigator to the CRO (Quintiles Pharmacovigilance) assigned by the Sponsor within 
24 hours by telephone and facsimile. 
Complete details of SAE contact information for Quintiles Pharmacovigilance will be 
provided to sites in each of the participating countries in the Study Reference Manual. 
A written report for an SAE must follow within 24 hours of the initial notification, including a 
full description of the event and any sequelae. This includes events that occur while enrolled 
in the study or within the Follow-Up Period. The Investigator shall comply with all applicable 
regulations and report all SAEs according to the requirements of their Institutional Review 
Board (IRB), Independent Ethics Committee (IEC) or Research Ethics Board (REB).  
11.4.1. 
Adverse Events Follow-Up  
AEs will be recorded from the start of this extension study (informed consent provided by 
patient at the Baseline visit) until 30 days after administration of the last dose of study 
medication (end of study medication taper-off). All post-treatment events will be collected 
through spontaneous reporting by the patient. All AEs and SAEs will be followed until the 
event resolves, the condition stabilizes, the event is otherwise explained, or the patient is 
lost to follow up. The Investigator is responsible for ensuring that follow up includes any 
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supplemental investigations as may be indicated to elucidate the nature and/or causality of 
the AE.  This may include additional laboratory tests or investigations, histopathological 
examinations, or consultation with other health care professionals, as is practical. 
12. DOSE MODIFICATIONS 
Patients will be treated with 600-1200 mg/day of retigabine as an adjunct therapy to their 
current antiepileptic medications (AEDs) or vagal nerve stimulation as established in Study 
VRX-RET-E22-302. 
If, in the opinion of the Investigator, the patient was not receiving the maximum effective 
dose, the dose could be increased in weekly intervals of 150 mg/day, up to a maximum of 
1200 mg daily (i.e. 400 mg TID). If adverse events considered to be secondary to retigabine 
occur, the total daily dose could be reduced by 150 mg/day every week, at Investigator 
discretion, as long as the dose is within 600-1200 mg/day. 
After the patient has entered open-label treatment, the Investigator may add new AEDs, as 
long as these are approved AEDs. In addition, the existing background AED therapy can be 
adjusted to achieve the best efficacy/safety ratio, as needed, per Investigator discretion. If 
necessary, in the Investigator’s judgment, all background AEDs can be discontinued to 
achieve monotherapy with retigabine. 
Patients who permanently discontinue open-label treatment will have their dose tapered by 
one-third every week. 
If a patient experiences a serious adverse event that is categorized to be “life-threatening,” 
all study medication must be discontinued immediately. 
All dose modifications and reason(s) must be documented in the patient’s source 
documents and the CRF. 
13. MONITORING 
The Sponsor or designee will monitor this clinical trial through visits scheduled to check the 
adequacy of staff and facilities, and to ensure adherence to the protocol, study procedures 
and applicable regulations. The clinical monitor will also assess proper CRF completion and 
retention. The Investigator and clinical staff are expected to allocate sufficient time to permit 
adequate review of the study’s progress. The Investigator will permit trial-related monitoring, 
audits, IRB/IEC review and regulatory inspection(s), providing direct access to source 
data/documents. 
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14. QUALITY ASSURANCE AND QUALITY CONTROL 
The Sponsor or designee will implement and maintain quality assurance and quality control 
systems with Standard Operating Procedures (SOPs) to ensure that this clinical trial is 
conducted and data are generated, documented (recorded) and reported in compliance to 
the protocol, Good Clinical Practice (GCP) standards, ICH and other applicable regulations. 
The Sponsor is responsible for securing agreement among collaborating parties to ensure 
direct access to clinical-trial-related sites and material to ensure that all data are reliable and 
have been processed correctly. 
15. DRUG ACCOUNTABILITY 
The Investigator must maintain accurate records of the study medication received from the 
Sponsor, including date received, number of units received and lot number. The Investigator 
must also ensure that the drug supplies are kept secured and accounted for with access 
limited to those authorized by the Investigator. The study coordinator or designee must 
maintain accurate records of all study medication received to be able to reconcile the 
dispensing logs at the end of the study. The study drug records must be readily available for 
inspection by the study monitor and/or auditor. No medication (new or used) can be returned 
to the Sponsor (or its designee) or disposed of at the research unit until the Sponsor’s 
clinical monitor has verified the accuracy of the study medication records at the site and 
indicated whether the medication should be destroyed at the site or returned to the Sponsor 
(or its designee), in which case the study monitor must indicate the name and address of the 
individual to whom the returned materials should be shipped. 
16.  LABELING AND PACKAGING OF STUDY MEDICATION 
The study drug will be packaged and labeled in a manner consistent with the study design 
and applicable regulations. The study drug shall be identified as an investigational 
compound. The study protocol number will be identified on the unit label. Designated site 
personnel shall record the drug unit on the drug dispensing logs when the study drug is 
dispensed. 
Each bottle of retigabine tablets (50 mg, 100 mg, or 300 mg per tablet) will be labeled with 
the protocol number, a unique package number, the name of the study medication, the use-
by date, the Valeant address, and any additional information required by local regulations.  
In addition, spaces will be included for recording patient number/initials, visit number, and 
dated dispensed. Specific dosage instructions will be provide separately to the patient.  A 
sufficient supply of study medication will be provided to each site for completion of trial, 
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based on the number of patients enrolled, study visit schedule, and the daily doses of 
patients. 
All study medication will be dispensed by the pharmacy or an appropriately qualified 
member of the study staff assigned by the Principal Investigator to this task. 
17. DATA HANDLING AND RECORDKEEPING 
17.1. Records 
The Investigator must maintain all documents and records, copies or originals, relating to 
the conduct of this trial. This documentation includes, but is not limited to protocols, CRFs, 
advertising for patient participation, AE reports, patient source data, correspondence with 
health authorities and IRB/IEC/REB, consent forms, Investigator’s curriculum vitae, monitor 
visit logs, laboratory reference ranges and laboratory certification or quality control 
procedures and laboratory director curriculum vitae. The Investigator and affiliated institution 
should maintain the trial documents as required by the applicable regulations. The 
Investigator and affiliated institution should take measures to prevent accidental or 
premature destruction of documents. Clinical trial documents must be kept in the clinical 
site’s archives indefinitely, unless written authorization is obtained from the Sponsor. 
Federal regulations require that records of drug disposition, CRFs, and all reports of this 
investigation shall be retained by the Investigator for a minimum of 15 years after notification 
by Valeant that the regulatory authorities have been notified of the study's termination, or 2 
years after approval of the marketing application.  If the Investigator is unable to retain the 
study documents for the required amount of time, Valeant must be informed of the individual 
who will be assuming this responsibility.  These documents shall be retained for a longer 
period, however, if required by applicable regulatory requirement(s) or if needed by the 
Sponsor. 
17.2. Case Report Forms 
All entries on a CRF are ultimately the responsibility of the Investigator, who is expected to 
review each form for completeness, accuracy and legibility before signing. All forms must be 
filled out by using black ink. Errors should be lined out but not obliterated and the correction 
inserted, initialed, dated and an explanation provided (if not evident). A CRF must be 
completed for each participant who has given informed consent. The CRFs and source 
documents must be made available to the study monitor for review at the time of the 
monitoring visits. 
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18. INSTITUTIONAL REVIEW BOARD 
This study is to be conducted in accordance with Institutional Review Board (IRB) 
regulations (US 21 CFR, Part 56) or applicable Independent Ethics Committee (IEC) 
regulations. The IRB/IEC must review and approve the following documents, if applicable: 
• 
Trial protocol and amendment(s). 
• 
Written informed consent form(s) and consent form updates. 
• 
Patient recruitment procedures (e.g., advertisements). 
• 
Written information to be provided to patients. 
• 
Investigator’s Brochure (IB) and available safety information. 
• 
Information about payments and compensation available to patients. 
The IRB/IEC approval should be in writing, clearly identifying the trial, the documents 
reviewed including informed consent and date of the review. The Investigator has the 
responsibility to provide the Sponsor with the written IRB/IEC approval prior to initiating any 
study-related procedures. The Investigator also has the responsibility to inform the IRB/IEC 
of serious and unexpected AEs and provide the IRB/IEC with a final report upon study 
completion.  
19. COMPLIANCE WITH THE DECLARATION OF HELSINKI 
This study is to be conducted in compliance with the Declaration of Helsinki (Appendix C). 
20. INFORMED CONSENT 
Prior to participation in a study, the patient or patient’s legal representative must sign an 
IRB/IEC approved written informed consent form. The approved written informed consent 
must abide to all applicable laws in regards to the safety and confidentiality of the patients. 
To obtain and document informed consent, the Investigator should comply with applicable 
regulations; adhere to GCP standards and the ethical principles in the Declaration of 
Helsinki (Appendix C). 
The language in the oral and written information about the trial, including the written 
informed consent form should be as non-technical as practical and should be 
understandable to the patient or patient’s legal representative and the impartial witness, 
where applicable. Before informed consent is obtained, the Investigator should provide the 
patient or patient’s legal representative ample time and opportunity to inquire about the trial 
and to decide whether or not to participate. 
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All questions about the trial should be answered to the satisfaction of the patient or the 
patient’s legal representative. The written informed consent form should be signed and 
personally dated by the patient or patient’s legal representative, and by the person who 
conducted the informed consent discussion. Patients will be informed that participation is 
voluntary and that he/she can withdraw from the study at any time. A signed copy of the 
consent form must be given to the patient, and this fact will be documented in the CRFs. 
21. CHANGES TO THE PROTOCOL 
The Investigator shall not implement any deviation or change to the protocol without 
approval by the Sponsor and prior review and documented approval and favorable opinion 
from the IRB/IEC/REB. The only exception is when it is necessary to eliminate immediate 
hazards to study patients or when changes involve only logistical or administrative aspects 
of the study (e.g., change in monitors, change in phone numbers). 
Although the Sponsor has every intention of completing the study, the Sponsor reserves the 
right to discontinue the study at any time for clinical or administrative reasons. 
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22. REFERENCES 
1. 
Rostock A, Tober C, Rundfeldt C, Bartsch R, Engel J, Polymeropoulos EE, et al. D-
23129: a new anticonvulsant with a broad spectrum activity in animal models of 
epileptic seizures. Epilepsy Res, 1996;23: 211-23. 
2. 
Tober C, Rostock A, Rundfeldt C, Bartsch R.  D-23129: a potent anticonvulsant in 
the amygdala kindling model of complex partial seizures. Eur J Pharmacol, 1996; 
303: 163-9. 
3. 
Armand V, Rundfeldt C, Heinemann U.  Effects of retigabine (D-23129) on different 
patterns of epileptiform activity induced by 4-aminopyridine in rat entorhinal cortex 
hippocampal slices. Naunyn Schmiedebergs Arch Pharmacol, 1999;359: 33-9. 
4. 
Armand V, Rundfeldt C, Heinemann U.  Effects of retigabine (D-23129) on different 
patterns of epileptiform activity induced by low magnesium in rat entorhinal cortex 
hippocampal slices. Epilepsia, 2000;41: 28-33. 
5. 
Wang HS, Pan Z, Shi W, Brown BS, Wymore RS, Cohen US, et al.  KCNQ2 and 
KCNQ3 potassium channel subunits: molecular correlates of the M-channel. 
Science, 1998;282: 1890-3. 
6. 
Rundfeldt C, Netzer R.  The novel anticonvulsant retigabine activates M-currents in 
Chinese hamster ovary-cells transfected with human KCNQ2/3 subunits. Neurosci 
Lett, 2000;281: 73-6. 
7. 
Main MJ, Cryan JE, Dupere JR, Cox B, Clare JJ, Burbidge SA, et al.  Modulation 
KCNQ2/3 potassium channels by the novel anticonvulsant retigabine. Mol 
Pharmacol, 2000;58: 253-62. 
8. 
Wickenden AD, Yu WF, Zou A, Jegla T, Wagoner PK, et al.  Retigabine, a novel 
anticonvulsant, enhances activation of KCNQ2/Q3 potassium channels. Mol 
Pharmacol, 2000;58: 591-600. 
9. 
Wickenden AD, Zou AR, Wagoner PK, Jegla T.  Characterization of KCNQ5/Q3 
potassium channels expressed in mammalian cells. Br J Pharmacol, 2001;132: 381-
4. 
10. 
Hirsch E, De Saint-Martin A, Marescaux C.  Benign neonatal familial convulsions: a 
model of idiopathic epilepsy. Rev Neurol (Paris), 1999;155: 463-7. 
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11. 
Rundfeldt C, Netzer R.  Investigation into the mechanism of action of the new 
anticonvulsant retigabine. Interaction with GABAergic and glutamatergic 
neurotransmission and with voltage gated ion channels. Arzneimittelforschung, 
2000;50: 1063-70. 
12. 
Kapetanovic IM, Rundfeldt C.  A new anticonvulsant compound. CNS Drug Rev, 
1996;2: 308-21. 
13. 
White HS, Wolf HH, Woodhead JH, Kupferberg HJ. The National Institutes of Health 
Anticonvulsant Drug Development Program: Screening for Efficacy. Antiepileptic 
Drug Development. Advances in Neurology, Vol. 6. edited by J French, I Leppik, and 
M Dichter. Lippincott-Raven Publishers, Philadelphia, PA, 1998, pp 29-39. 
14. 
 Effect of D-23129 against amygdala kindled seizures. Report #: D-23129-
FP0295, 1995. 
15. 
 D23129: Investigation of possible abuse potential. Report #: D-23129-1995. 
16. 
 D-23129, GKE-841: Single dose oral (gavage) 
toxicokinetic study in mice. Report #: D-23129-9321020016, 1999. 
17. 
 Amended document: D-23129: Absolute systemic bioavailability and 
pharmacokinetics following single oral or i.v. administration to Wistar rats. Report #: 
D-23129-FBDD0795, 1998. 
18. 
 Amended document: Metabolism of [14C]D-23129 in rats and dogs after 
oral dosing of 8.25 mg/kg. Report #: D-23129/FB20196, 1998. 
19. 
 Exploratory investigations on the in-vivo metabolism of D-23129 in plasma 
of rats and dogs and on metabolite pharmacokinetics in rats. Report #: D-
23129/FBDD0494, 1995. 
20. 
 
 In vitro and in vivo metabolism of D-23129 in man. Report #: 
D-23129/FB20396, 1996. 
21. 
 Amended document: Pharmacokinetics of D-23129 in rats following a 
single oral dose administration of the 14C-labeled drug. Report #: D-
23129/FBDD1095, 1999. 
22. 
 Amended Document: D-23129: Pharmacokinetics in Wistar rats 
following single oral administration of [U-14C]D-23129 at 8.25 mg/kg. Report #: D-
23129/FB20297, 1998. 
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23. 
 D-23129: Pharmacokinetics in Beagle dogs following single oral 
administration of [U-14C]D-23129 at 8.25 /kg. Report #: D-23129/FBDD0995a, 1997. 
24. 
 The effect of valproic acid on retigabine glucuronidation in 
human liver microsomes. Report #: D-23129/FB20100, 2000. 
25. 
 The effect of imipramine or lamotrigine on retigabine 
glucuronidation in human liver microsomes. Report #: D-23129/FB20399, 1999. 
26. 
 Determination of interactions of D-23129 with the antiepileptic standards 
carbamazepine, sodium valproate and phenytoin. Report #: D-23129/FP0496, 1995. 
27. 
 Interaction of D-23129 with carbamazepine, valproate and phenytoin in rats 
Report #: D-23129/FP129, 1997. 
28. 
 Anticonvulsant and neurotoxic potencies of D-23129 in the threshold 
models in male mice and female rats. Report #: D-23129/FP2495, 1994. 
29. 
 Electrophysiological effects of RETIGABINE and its monoacetyl 
metabolite WAY-163980 on cat myocytes and dog Purkinje fibers. Report #: D-
23129/1020107, 1999. 
30. 
 Examination of the effects of retigabine on KCNQ1/KCNE1- and on 
HERG-mediated potassium currents receptor subtypes. Report #: D-
23129/FP10500, 1999. 
31. 
 Retigabine: A multiple oral dose cardiovascular study in conscious male 
and female dogs. Report #: D-23129/9321020, 1999. 
32. 
 Effects of retigabine (WAY-143841) on experimental bladder instability 
in the rat. Report #: D-23129/9321020109, 2001. 
33. 
 Testing the acute toxicity after single oral administration in rats. Report #: 
D-23129/3000912460, 1999. 
34. 
 Amended document: D-23129: 5-Week oral toxicity study after repeated 
administration in rats and subsequent 6-week recovery period. Report #: D-
23129/3000900540, 1995. 
35. 
 Complete amended document: Retigabine: 13 
week oral (diet) toxicity study in B6C3F1 mice (amended version 1.1). Report #: D-
23129/3000922904, 2000. 
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36. 
 Retigabine: 28-day oral (t.i.d. capsule) toxicity study in dogs. Report 
#: D-23129/9321020031, 2002. 
37. 
 Amended document: Amendment No. 2 to the report: D-
23129: 13-Week oral toxicity study after repeated administration in beagle dogs and 
subsequent 6-week recovery period. Report #: D-23129/3000896861, 1996.  
38. 
 Examination of the influence of D-23129 on the pregnant rat and the 
fetus by oral administration. Report #: D-23129/3000911733, 1998. 
39. 
 Examination of the influence of D-23129 on the pregnant rabbit and the 
fetus by oral administration, Report #: D-23129/3000911722, 1998. 
40. 
 Retigabine: Oral (gavage) perinatal and postnatal 
toxicity study with behavioral and reproductive assessments of offspring in rats. 
Report #: D-23129/9321020048, 2000. 
41. 
 Retigabine: Two-month oral 
(gavage) toxicity study with recovery in juvenile rats. Report #: D-
23129/9321020106, 2000. 
42. 
 Mutagenicity study of DFB-Retigabine-Oxalate in the Salmonella 
Typhimurium reverse Report #: D-23129/9321020151, 2002. 
43. 
 Salmonella typhimurium reverse mutation assay influence of 
Salmonella typhimurium substrains and S-9 batches on mutagenicity data of 
retigabine (batch 9805004) Report #: D-23129/3000922533, 2001. 
44. 
 CHO/HPRT mammalian mutagenicity assay with D-23129.  Report #: 
D-23129/3000914286, 1997. 
45. 
 Chromosome aberration assay in human blood lymphocytes with D-
23129. Report #: D-23129/3000914297, 1997. 
46. 
 Amended document: In vivo bone marrow cytogenetic test of D-20443 
by oral administration to Sprague-Dawley rats (chromosomal analysis), (date of 
report: April 16, 1993). Report #: D-20443/3000893856, 1997. 
47. 
 In vivo mouse bone marrow erythrocyte micronucleus assay with D-
23129. Report #: D-23129/3000914308, 1997. 
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48. 
 D-20443: Mouse micronucleus test (single oral administration) Report #: 
D-20443/3000887657, 1992. 
49. 
 Ascending multiple dose tolerance study of 
retigabine (GKE-841) in healthy male subjects - Ascending, double-blind (unblinded 
third part), placebo-controlled multiple-dose study in healthy male subjects (Study 
no: 3065A1-102-US) Report #: D-23129/9359000010, 2001. 
50. 
 Retigabine N-glucuronidation and its potential role in enterohepatic 
circulation. Report #: D-23129/FB23000, 2001. 
51. 
 In vitro and in vivo metabolism of D-23129 in Man. Report #: 
D-23129/FB20396, 1996. 
52. 
 3065A1-205-EU/AU/US:  A randomized, double-
blind, placebo-controlled, parallel group, multicenter, dose-ranging, efficacy and 
safety study of retigabine (D-23129, GKE-841) administered as add-on therapy in 
subjects with partial epilepsy. Report #: D-23129/9352000001, 2003. 
53. 
Hempel R, Schupke H, McNeilly PJ, et al. Metabolism of retigabine (D-23129, a 
novel anticonvulsant. Drug Metab Disp, 1999; 27:605-612. 
54. 
 D-23129-8001/D-23129-8005 (03065A1-200-
EU/03065A1-201-EU)Efficacy, Tolerability, Safety and Pharmacokinetics/ Steady 
State Kinetics or Orally Administered Retigabine (GKE-841, D-23129) in Patients 
with Partial Onset Seizures. Report #: D023129/ 9352000002.  
55. 
 3065A1-202-US: A multicenter, open-label, 
safety, tolerability and preliminary efficacy study of GKE-841 (RETIGABINE, D-
23129) administered as add-on therapy to subjects with epilepsy currently receiving 
monotherapy with an established anticonvulsant agent. Report #: CSR-42037, 2002. 
56. 
Investigator’s Brochure. Retigabine (D-23129), Valeant Research & Development, 
Edition Number 6, 13 June 2005. 
 
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Appendix A. Study Flow Chart 
Baseline1 
Open-Label Extension – First Year2,3 
Open-Label Extension - Second Year and Onward2,3 
Visit 0  
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 54 
Visit 6 
Visit 7 
Visit 84 
Visit 9 
Visit 
10 
Visit 
114 
Study Procedures 
Month 0 
Month 
1 
Month 
3  
Month 
6 
Month 
9 
Month 
12 
Month 
16 
Month 
20 
Month 
24 
Month 
28 
Month 
32 
Month 
36 
Eligibility/Informed 
Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
Physical and 
Neurological Exam 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
Brief Neurological 
Exam 
 
X 
X 
X 
X 
 
X 
X 
 
X 
X 
 
Vital Signs (BP, 
HR, and 
Temperature) and 
Weight5 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12 Lead ECG 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
Blood Chemistry 
and Hematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urinalysis 
(including 
Microscopy) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AUA Symptom 
Index7 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
PVR Bladder 
Ultrasound7 
X 
X 
X 
 
 
X 
 
 
 
 
 
 
Serum Pregnancy 
Test6 
X 
 
 
 
 
X 
 
 
X 
 
 
X 
Seizure Diary 
Review 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
AE Evaluation 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
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Baseline1 
Open-Label Extension – First Year2,3 
Open-Label Extension - Second Year and Onward2,3 
Visit 0  
Visit 1 
Visit 2 
Visit 3 
Visit 4 
Visit 54 
Visit 6 
Visit 7 
Visit 84 
Visit 9 
Visit 
10 
Visit 
114 
Study Procedures 
Month 0 
Month 
1 
Month 
3  
Month 
6 
Month 
9 
Month 
12 
Month 
16 
Month 
20 
Month 
24 
Month 
28 
Month 
32 
Month 
36 
Concomitant 
Medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
QOLIE-31-P 
Questionnaire 
X 
 
X 
X 
X 
X 
 
 
X 
 
 
X 
Dispense Open-
Label Study 
Medication8 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Collect Returned 
Open-Label Study 
Medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
1. 
Baseline for the open-label extension study corresponds to the assessments performed at the last visit of the Maintenance phase (Visit 9) of Study VRX-
RET-E22-302 for all patients.  The final, baseline eligibility assessment for the open-label extension study, including obtaining informed consent and 
dispensing open-label study medication will be performed at the last visit of the Transition phase (Visit 11) of Study VRX-RET-E22-302. 
2. 
Study Visit 1 will have a window range of ±3 days. After Study Visit 1, all remaining study visits will have a window range of ±7 days around that visit day to 
accommodate individual schedules. Each study month will be defined as 30 calendar days. If a patient visit occurs outside the visit window, the study clinical 
monitor (CRA) should be notified and the reason for the deviation noted. An attempt should be made to ensure that the patient returns for subsequent visits 
on schedule using the last visit of the Transition phase (Visit 11) of Study VRX-RET-E22-302, which corresponds to the final, Baseline eligibility visit for the 
open-label extension study. 
3. 
This open-label extension study will be continued until retigabine is approved and commercially available, or until the program is discontinued, followed by a 
3-week tapering period and a 30 day post-study period for collection of adverse events.  After the first year, the study visits will occur every 4 months (3 visits 
per year).  After the first year, the assessments for the first 2 study visits of each year (e.g. Visits 6, 7, 9 and 10) will be identical, and the assessments for the 
last study visit of each year (e.g. Visits 8 and 11) will be identical.   
4. 
All patients who discontinue early from study treatment during the open-label extension study will have their study medication tapered over a 3-week period, 
reducing their daily dose by one-third per week, and then return for a final visit.  Patients who discontinue early during the first year of the open-label 
extension study will complete all assessments and evaluations scheduled for Study Visit 5.  Patients who discontinue early during the second year of the 
open-label extension study will complete all assessments and evaluations scheduled for Study Visit 8.  Patients who discontinue early during the third year of 
the open-label extension study will complete all assessments and evaluations scheduled for Study Visit 11.  Also, all adverse events should be followed and 
collected up to until 30 days after administration of the last dose of study drug (end of study drug taper-off). 
5. 
Supine and standing blood pressure, heart rate. 
6. 
In addition to the scheduled pregnancy tests, a pregnancy test should be performed during the study whenever a woman’s menstrual period is 5 days late. 
7. 
The AUA Symptom Index and the PVR bladder ultrasound will only be performed during the first year of the open-label extension study (Visits 1, 2, and 5).   
8. 
Dispensation of study medication is not applicable at the final study visit, if a patient has discontinued early or completed the open-label extension study.
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Appendix B. World Medical Association Declaration 
of Helsinki 
Ethical Principles for Medical Research Involving Human Subjects 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964, and amended 
by the 
29th WMA General Assembly, Tokyo, Japan, October 1975 
35th WMA General Assembly, Venice, Italy, October 1983 
41st WMA General Assembly, Hong Kong, September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
and the 52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
Note of Clarification on Paragraph 29 added by the WMA General Assembly, Washington 
2002 
Note of Clarification on Paragraph 30 added by the WMA General Assembly, Tokyo 2004 
 
INTRODUCTION 
1. The World Medical Association has developed the Declaration of Helsinki as a statement 
of ethical principles to provide guidance to physicians and other participants in medical 
research involving human subjects. Medical research involving human subjects includes 
research on identifiable human material or identifiable data. 
2. It is the duty of the physician to promote and safeguard the health of the people. The 
physician's knowledge and conscience are dedicated to the fulfillment of this duty. 
3. The Declaration of Geneva of the World Medical Association binds the physician with the 
words, "The health of my patient will be my first consideration," and the International 
Code of Medical Ethics declares that, "A physician shall act only in the patient's interest 
when providing medical care which might have the effect of weakening the physical and 
mental condition of the patient."  
4. Medical progress is based on research which ultimately must rest in part on 
experimentation involving human subjects. 
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5. In medical research on human subjects, considerations related to the well-being of the 
human subject should take precedence over the interests of science and society. 
6. The primary purpose of medical research involving human subjects is to improve 
prophylactic, diagnostic and therapeutic procedures and the understanding of the 
aetiology and pathogenesis of disease. Even the best proven prophylactic, diagnostic, 
and therapeutic methods must continuously be challenged through research for their 
effectiveness, efficiency, accessibility and quality. 
7. In current medical practice and in medical research, most prophylactic, diagnostic and 
therapeutic procedures involve risks and burdens. 
8. Medical research is subject to ethical standards that promote respect for all human 
beings and protect their health and rights. Some research populations are vulnerable 
and need special protection. The particular needs of the economically and medically 
disadvantaged must be recognized. Special attention is also required for those who 
cannot give or refuse consent for themselves, for those who may be subject to giving 
consent under duress, for those who will not benefit personally from the research and for 
those for whom the research is combined with care. 
9. Research Investigators should be aware of the ethical, legal and regulatory requirements 
for research on human subjects in their own countries as well as applicable international 
requirements. No national ethical, legal or regulatory requirement should be allowed to 
reduce or eliminate any of the protections for human subjects set forth in this 
Declaration. 
BASIC PRINCIPLES FOR ALL MEDICAL RESEARCH 
10. It is the duty of the physician in medical research to protect the life, health, privacy, and 
dignity of the human subject. 
11. Medical research involving human subjects must conform to generally accepted 
scientific principles, be based on a thorough knowledge of the scientific literature, other 
relevant sources of information, and on adequate laboratory and, where appropriate, 
animal experimentation. 
12. Appropriate caution must be exercised in the conduct of research which may affect the 
environment, and the welfare of animals used for research must be respected. 
13. The design and performance of each experimental procedure involving human subjects 
should be clearly formulated in an experimental protocol. This protocol should be 
submitted for consideration, comment, guidance, and where appropriate, approval to a 
specially appointed ethical review committee, which must be independent of the 
Investigator, the sponsor or any other kind of undue influence. This independent 
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committee should be in conformity with the laws and regulations of the country in which 
the research experiment is performed. The committee has the right to monitor ongoing 
trials. The researcher has the obligation to provide monitoring information to the 
committee, especially any serious adverse events. The researcher should also submit to 
the committee, for review, information regarding funding, sponsors, institutional 
affiliations, other potential conflicts of interest and incentives for subjects. 
14. The research protocol should always contain a statement of the ethical considerations 
involved and should indicate that there is compliance with the principles enunciated in 
this Declaration. 
15. Medical research involving human subjects should be conducted only by scientifically 
qualified persons and under the supervision of a clinically competent medical person. 
The responsibility for the human subject must always rest with a medically qualified 
person and never rest on the subject of the research, even though the subject has given 
consent. 
16. Every medical research project involving human subjects should be preceded by careful 
assessment of predictable risks and burdens in comparison with foreseeable benefits to 
the subject or to others. This does not preclude the participation of healthy volunteers in 
medical research. The design of all studies should be publicly available. 
17. Physicians should abstain from engaging in research projects involving human subjects 
unless they are confident that the risks involved have been adequately assessed and 
can be satisfactorily managed. Physicians should cease any investigation if the risks are 
found to outweigh the potential benefits or if there is conclusive proof of positive and 
beneficial results. 
18. Medical research involving human subjects should only be conducted if the importance 
of the objective outweighs the inherent risks and burdens to the subject. This is 
especially important when the human subjects are healthy volunteers. 
19. Medical research is only justified if there is a reasonable likelihood that the populations 
in which the research is carried out stand to benefit from the results of the research. 
20. The subjects must be volunteers and informed participants in the research project. 
21. The right of research subjects to safeguard their integrity must always be respected. 
Every precaution should be taken to respect the privacy of the subject, the confidentiality 
of the patient's information and to minimize the impact of the study on the subject's 
physical and mental integrity and on the personality of the subject. 
22. In any research on human beings, each potential subject must be adequately informed 
of the aims, methods, sources of funding, any possible conflicts of interest, institutional 
affiliations of the researcher, the anticipated benefits and potential risks of the study and 
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the discomfort it may entail. The subject should be informed of the right to abstain from 
participation in the study or to withdraw consent to participate at any time without 
reprisal. After ensuring that the subject has understood the information, the physician 
should then obtain the subject's freely-given informed consent, preferably in writing. If 
the consent cannot be obtained in writing, the non-written consent must be formally 
documented and witnessed. 
23. When obtaining informed consent for the research project the physician should be 
particularly cautious if the subject is in a dependent relationship with the physician or 
may consent under duress. In that case the informed consent should be obtained by a 
well-informed physician who is not engaged in the investigation and who is completely 
independent of this relationship. 
24. For a research subject who is legally incompetent, physically or mentally incapable of 
giving consent or is a legally incompetent minor, the Investigator must obtain informed 
consent from the legally authorized representative in accordance with applicable law. 
These groups should not be included in research unless the research is necessary to 
promote the health of the population represented and this research cannot instead be 
performed on legally competent persons. 
25. When a subject deemed legally incompetent, such as a minor child, is able to give 
assent to decisions about participation in research, the Investigator must obtain that 
assent in addition to the consent of the legally authorized representative. 
26. Research on individuals from whom it is not possible to obtain consent, including proxy 
or advance consent, should be done only if the physical/mental condition that prevents 
obtaining informed consent is a necessary characteristic of the research population. The 
specific reasons for involving research subjects with a condition that renders them 
unable to give informed consent should be stated in the experimental protocol for 
consideration and approval of the review committee. The protocol should state that 
consent to remain in the research should be obtained as soon as possible from the 
individual or a legally authorized surrogate. 
27. Both authors and publishers have ethical obligations. In publication of the results of 
research, the Investigators are obliged to preserve the accuracy of the results. Negative 
as well as positive results should be published or otherwise publicly available. Sources 
of funding, institutional affiliations and any possible conflicts of interest should be 
declared in the publication. Reports of experimentation not in accordance with the 
principles laid down in this Declaration should not be accepted for publication. 
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ADDITIONAL PRINCIPLES FOR MEDICAL RESEARCH COMBINED WITH 
MEDICAL CARE 
28. The physician may combine medical research with medical care, only to the extent that 
the research is justified by its potential prophylactic, diagnostic or therapeutic value. 
When medical research is combined with medical care, additional standards apply to 
protect the patients who are research subjects. 
29. The benefits, risks, burdens and effectiveness of a new method should be tested against 
those of the best current prophylactic, diagnostic, and therapeutic methods. This does 
not exclude the use of placebo, or no treatment, in studies where no proven 
prophylactic, diagnostic or therapeutic method exists.1 
30. At the conclusion of the study, every patient entered into the study should be assured of 
access to the best proven prophylactic, diagnostic and therapeutic methods identified by 
the study.2 
31. The physician should fully inform the patient which aspects of the care are related to the 
research. The refusal of a patient to participate in a study must never interfere with the 
patient-physician relationship. 
32. In the treatment of a patient, where proven prophylactic, diagnostic and therapeutic 
methods do not exist or have been ineffective, the physician, with informed consent from 
the patient, must be free to use unproven or new prophylactic, diagnostic and 
therapeutic measures, if in the physician's judgment it offers hope of saving life, re-
establishing health or alleviating suffering. Where possible, these measures should be 
made the object of research, designed to evaluate their safety and efficacy. In all cases, 
new information should be recorded and, where appropriate, published. The other 
relevant guidelines of this Declaration should be followed. 
 
 
1 Note of clarification on paragraph 29 of the WMA Declaration of Helsinki 
The WMA hereby reaffirms its position that extreme care must be taken in making use of a 
placebo-controlled trial and that in general this methodology should only be used in the 
absence of existing proven therapy. However, a placebo-controlled trial may be ethically 
acceptable, even if proven therapy is available, under the following circumstances: 
- Where for compelling and scientifically sound methodological reasons its use is necessary 
to determine the efficacy or safety of a prophylactic, diagnostic or therapeutic method; or 
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- Where a prophylactic, diagnostic or therapeutic method is being investigated for a minor 
condition and the patients who receive placebo will not be subject to any additional risk of 
serious or irreversible harm. 
All other provisions of the Declaration of Helsinki must be adhered to, especially the need 
for appropriate ethical and scientific review. 
 
2 Note of clarification on paragraph 30 of the WMA Declaration of Helsinki 
The WMA hereby reaffirms its position that it is necessary during the study planning process 
to identify post-trial access by study participants to prophylactic, diagnostic and therapeutic 
procedures identified as beneficial in the study or access to other appropriate care. Post-trial 
access arrangements or other care must be described in the study protocol so the ethical 
review committee may consider such arrangements during its review. 
9.10.2004 
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Appendix C. American Urological Association Symptom 
Index 
Reference: 
Barry MJ, et al. (1992). The American Urological Association symptom index for benign 
prostatic hyperplasia. Journal of Urology, 148: 1549–1557. 
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This section contained Clinical Outcome Assessment data collection questionnaires or indices, which are 
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Appendix D. Protocol Agreement 
PROTOCOL TITLE: 
A multicenter, open-label, long-term, safety, tolerability and efficacy study of retigabine in 
adult epilepsy patients with partial-onset seizures (Extension of study VRX-RET-E22-302). 
 
PROTOCOL NO: 
VRX-RET-E22-304 
This document is a confidential communication of Valeant Research & Development. The 
authorized Investigator agrees to personally conduct or supervise the conduct of this study 
as outlined in the current protocol. No changes will be made to the protocol without prior 
written approval from Valeant Research & Development, except to protect the safety, rights 
and welfare of the study participants and always in compliance with all applicable Good 
Clinical Practices (GCP), as well as International Conference on Harmonization (ICH) and 
regulatory requirements. Acceptance of this document constitutes the agreement by the 
Investigator that no unpublished information contained herein will be published or disclosed 
without prior written approval from Valeant Research & Development. 
I have read this protocol in its entirety and agree to conduct the study accordingly. 
 
 
______________________________________________ 
_________________ 
Signature: 
Date 
Principal Investigator 
 
 
______________________________________________ 
Printed Name 
 
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SAP_001.pdf: 
PAREXEL International, Durham, NC 27713 
 
Valeant Pharmaceuticals North America 
VRX-RET-E22-304 
A multicenter, open-label, long-term, safety, tolerability and efficacy study of retigabine 
in adult epilepsy patients with partial-onset seizures 
(Extension of Study VRX-RET-E22-302) 
Statistical Analysis Plan 
Version 2.0 [Final] 
Date: February 26, 2007
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Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
Filename: 87272_304_SAP_v2_final 
 
page 3 of 148 
 
 
TABLE OF CONTENTS 
 
1 
INTRODUCTION....................................................................................................... 5 
2 
STUDY OBJECTIVES ............................................................................................... 6 
3 
INVESTIGATIONAL PLAN ..................................................................................... 6 
3.1 Overall Study Design and Plan............................................................................. 6 
3.2 Efficacy and Safety Variables .............................................................................. 6 
3.2.1 Efficacy Assessments.................................................................................. 6 
3.2.2 Safety Assessments..................................................................................... 9 
3.2.3 Quality of Life Assessments....................................................................... 9 
4 
STATISTICAL METHODS ....................................................................................... 9 
4.1 Study Patients ....................................................................................................... 9 
4.1.1 Disposition of Patients................................................................................ 9 
4.1.2 Analysis Populations................................................................................. 10 
4.2 Demographic and Other Baseline Characteristics .............................................. 10 
4.3 General Considerations....................................................................................... 11 
4.4 Efficacy Evaluation ............................................................................................ 12 
4.5 Safety Evaluation................................................................................................ 13 
4.5.1 Extent of Exposure.................................................................................... 13 
4.5.2 Adverse Events ......................................................................................... 13 
4.5.3 Deaths, Serious Adverse Events, and Other Significant Adverse Events. 17 
4.5.4 Clinical Laboratory Evaluation................................................................. 18 
4.5.5 Vital Signs, Physical Findings and Other Observations Related to Safety18 
4.5.5.1 Vital Sign Measurements ............................................................ 18 
4.5.5.2 ECG............................................................................................. 19 
4.5.5.3 Physical and Neurological Examination ..................................... 19 
4.5.5.4 AUA Symptom Index.................................................................. 20 
4.5.5.5 Post-void Residual (PVR) Bladder Ultrasound........................... 20 
4.5.6 Concomitant Medications......................................................................... 20 
4.6 Quality of Life in Epilepsy (QOLIE-31-P)......................................................... 21 
4.7 Determination of Sample Size............................................................................ 21 
4.8 Changes in the Conduct of the Study or Planned Analysis ................................ 21 
5 
REFERENCES.......................................................................................................... 21 
6 
REPORTING OUTPUT............................................................................................ 21 
7 
LIST OF TABLES .................................................................................................... 23 
8 
LIST OF FIGURES................................................................................................... 27 
9 
LIST OF PATIENT DATA LISTINGS.................................................................... 28 
10 TABLE SHELLS ...................................................................................................... 30 
11 FIGURE SHELLS..................................................................................................... 87 
12 PATIENT DATA LISTING SHELLS...................................................................... 89 
 
 
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LIST OF ABBREVIATIONS 
 
AE 
Adverse event 
AED 
Antiepileptic drug 
ALT 
Alanine transaminase (SGPT) 
AST 
Aspartate transaminase (SGOT) 
AUA 
American Urological Association 
BMI 
Body mass index 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
CRA 
Clinical monitor 
CRF 
Case Report Form 
ECG 
Electrocardiogram 
ICH 
International Conference of Harmonization 
MedDRA® 
Medical Dictionary for Regulatory Activities 
ODS 
Output Delivery System 
OLE 
Open-label extension 
PVR 
Post-void Residual 
QTc 
QT correction  
RBC 
Red blood cell 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS® 
Statistical Analysis Software 
SD 
Standard deviation 
TEAE 
Treatment-emergent adverse event 
TID 
Three time a day 
WBC 
White blood cell 
WHO 
World Health Organization 
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1 
INTRODUCTION 
Epilepsy is among the most common neurological disorders, affecting approximately 50 
million people worldwide. Classical antiepileptic drugs (AEDs) currently provide 
satisfactory seizure control in approximately 70% of patients; however, the remaining 
30% of epilepsy patients are refractory to treatment. The partial onset seizure is the most 
common type of seizure that is uncontrolled in adult patients. The introduction of new 
AEDs 
(e.g., 
vigabatrin, 
lamotrigine, 
gabapentin, 
topiramate, 
levetiracetam, 
oxcarbazepine, zonisamide, and felbamate) during the last decade has increased 
therapeutic possibilities. However, data from recent clinical trials demonstrate that none 
of the newer AEDs provides adequate seizure control in all patients. The treatment of 
patients that do not respond to current AEDs remains a problem and motivates the 
continued search for compounds with high antiepileptic potential and low rates of side 
effects. 
 
Retigabine 
(GKE-841 
or 
D-23129), 
N-[2-amino-4(4-fluorobenzylamino)-phenyl] 
carbamic acid ethyl ester, is a new chemical entity discovered by ASTA Medica, 
Germany, and was acquired by Valeant Research & Development (Valeant) for 
development as an AED for the treatment of partial onset seizures. It is a deaza analog of 
flupirtine, currently marketed in some regions as a centrally acting analgesic with 
ancillary muscle relaxing properties. 
 
Two Phase 3 studies (VRX-RET-E22-301 and VRX-RET-E22-302) to compare the 
efficacy and safety of retigabine (600 mg/day, 900 mg/day, or 1200 mg/day) to placebo 
as an adjunctive therapy in refractory patients with partial-onset seizures are currently 
being conducted. These studies are randomized, double-blind, placebo-controlled, multi-
center, parallel-group trials enrolling a total of approximately 790 patients, globally. 
Because of the serious nature of epilepsy, the retigabine clinical program had foreseen 
that all patients who enter and complete a Phase 3 study with retigabine will be given the 
opportunity to continue treatment, if they consent and if the Principal Investigator feels 
they can benefit from continued retigabine treatment.  Hence, an open-label extension 
protocol was designed for each double-blind study. 
 
This study is the open-label extension of the Phase 3 Study VRX-RET-E22-302. VRX-
RETE22-302 is a randomized, double-blind, placebo-controlled, parallel-group, 
multicenter, study of 900 mg/day and 600mg/day retigabine versus placebo. During the  
4-week titration phase patients are titrated to the target dose. 510 patients are expected to 
be randomized to treatment. A 12-week maintenance phase follows. All patients who 
wish to enter the open-label extension protocol will enter a 4-week transition phase in 
which their dose will be titrated to 300 mg TID in order to maintain the blind to the 
maximum extent. Thereafter, the patients could enter this extension study (Study VRX-
RET-E22-304). Patients who do not wish to enter the open-label extension protocol will 
have their dose tapered over a 3-week period. 
 
This Statistical Analysis Plan (SAP) was created according to Protocol VRX-RET-E22-
304, Amendment 1 (July 2, 2007). 
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2 
STUDY OBJECTIVES 
Primary Objective  
 
To evaluate the safety and tolerability of long-term therapy with retigabine administered 
as adjunctive therapy in adult epilepsy patients with partial-onset seizures, who 
completed the double-blind Study VRX-RET-E22-302. 
 
Secondary Objective 
 
To evaluate efficacy of long-term treatment with retigabine and patient quality of life, 
evaluated through the QOLIE-31-P questionnaire. 
 
3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
This is an open-label extension study of the placebo controlled, double-blind Study 
VRXRET-E22-302. Patients will be treated with 600 - 1200 mg/day of retigabine as an 
adjunct therapy to their current antiepileptic medications (AEDs) or vagal nerve 
stimulation as established in Study VRX-RET-E22-302. Following completion of the 
Transition Phase of the double-blind study (Study VRX-RET-E22-302), treatment in this 
open-label extension study will be continued until retigabine is approved and 
commercially available, or until the program is discontinued, followed by a 3-week 
tapering period and a 30 day post-study period for collection of adverse events. 
 
 
3.2 
Efficacy and Safety Variables 
A study flow chart summarizing all study procedures can be found in Table 1.  
 
3.2.1 Efficacy Assessments 
Patients will keep a seizure diary throughout the study. The anticonvulsant efficacy of 
retigabine will be evaluated by comparison of baseline seizure frequency (obtained 
during the 8-week baseline period of Study VRX-RET-E22-302) with seizure frequency 
obtained during retigabine therapy in this open-label extension study (VRX-RET-E22-
304).   The primary efficacy variable is the percentage change in the monthly seizure rate 
from the baseline phase to the open-label treatment phase.  The proportion of responders 
(patients experiencing ≥ 50% reduction in seizure frequency) from baseline to the open-
label treatment phase will be evaluated. 
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Table 1: Study Flow Chart 
 
Study Procedures 
Baseline1 
Open-Label Extension-First Year2,3 
Open-Label Extension-Second 
Year and Onward2,3 
Visit 
0 
1 
1a9 
2 
2a9 
3 
3a9 
4 
4a9 
54 
6 
7 
84 
9 
10 
114 
Month in Study 
0 
1 
2 
3 
4 
6 
8 
9 
10 
12 
16 
20 
24 
28 
32 
36 
Eligibility /ICF 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical & Neuro Exam 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Brief Neuro Exam 
 
X 
 
X 
 
X 
 
X 
 
 
X 
X 
 
X 
X 
 
Vital Signs (BP,HR,&Temp) 
&Wt5 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
12 Lead ECG 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
Blood Chem and Hematology 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Hematological Evaluation 
 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
 
 
 
Urinalysis (including Microscopy) 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
AUA Symptom Index7 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
PVR Bladder Ultrasound 
X 
X 
 
X 
 
 
 
 
 
X 
 
 
 
 
 
 
Serum Preg Test6 
X 
 
 
 
 
 
 
 
 
X 
 
 
X 
 
 
X 
Urine Preg Test6 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Seizure Diary Review 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
AE Evaluation 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
QOLIE-31-P Qx 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
 
X 
Dispense OLE Study Meds8 
X 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
Collected Returned OLE Study 
Meds 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
 
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Table 1: Study Flow Chart (continued) 
 
1. Baseline for the open-label extension study corresponds to the assessments performed at the last visit of the Maintenance phase (Visit 9) 
of Study VRX-RET-E22-302 for all patients. The final, baseline eligibility assessment for the open-label extension study, including 
obtaining informed consent and dispensing open-label study medication will be performed at the last visit of the Transition phase (Visit 11) 
of Study VRX-RET-E22-302. 
2. Study Visit 1 will have a window range of ±3 days. After Study Visit 1, all remaining study visits will have a window range of 7 days around 
that visit day to accommodate individual schedules.  Each study month will be defined as 30 calendar days. If a patient visit occurs outside 
the visit window, the study clinical monitor (CRA) should be notified and the reason for the deviation noted. An attempt should be made to 
ensure that the patient returns for subsequent visits on schedule using the last visit of the Transition phase (Visit 11) of Study VRX-RET-
E22-302, which corresponds to the final, Baseline eligibility visit for the open-label extension study. 
3. This open-label extension study will be continued until retigabine is approved and commercially available, or until the program s 
discontinued, followed by a 3-week tapering period and a 30 day post-study period for collection of adverse events. After the first year, the 
study visits will occur every 4 months (3 visits per year). After the first year, the assessments for the first 2 study visits of each year (e.g. 
Visits 6, 7, 9 and 10) will be identical, and the assessments for the last study visit of each year (e.g. Visits 8 and 11) will be identical. 
4. All patients who discontinue early from study treatment during the open-label extension study will have their study medication tapered over 
a 3-week period, reducing their daily dose by one third per week, and then return for a final visit. Patients who discontinue early during the 
first year of the open-label extension study will complete all assessments and evaluations scheduled for Study Visit 5. Patients who 
discontinue early during the second year of the open-label extension study will complete all assessments and evaluations scheduled for 
Study Visit 8. Patients who discontinue early during the third year of the open-label extension study will complete all assessments and 
evaluations scheduled for Study Visit 11. Also, all adverse events should be followed and collected up to until 30 days after administration 
of the last dose of study drug (end of study drug taper-off). 
5. Supine and standing blood pressure, heart rate. 
6. In addition to the scheduled pregnancy tests, a pregnancy test should be performed during the study whenever a woman’s menstrual 
period is 5 days late. 
7. The AUA Symptom Index and the PVR bladder ultrasound will only be performed during the first year of the open-label extension study 
(Visits 1, 2, and 5). 
8. Dispensation of study medication is not applicable at the final study visit, if a patient has discontinued early or completed the open-label 
extension study. 
9. Study visits added per FDA comments that the open label extension trial should include more frequent hematological monitoring. These 
are now in-line with the hematological monitoring frequencies per the VRX-RET-E22-302, double-blind trial. 
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3.2.2 Safety Assessments 
Safety assessments will be evaluated, based on reports of AEs and results of vital signs 
(supine and standing blood pressure, pulse, and temperature), weight, clinical laboratory 
evaluations (blood chemistries, hematology and urinalysis including microscopy), a 12-
lead ECG, and physical and neurological examinations. Post-void residual (PVR) bladder 
ultrasounds to assess urinary retention and the American Urological Association (AUA) 
Symptom Index to assess urinary voiding function will also be performed during the first 
year of the open-label extension study. 
 
3.2.3 Quality of Life Assessments 
The QOLIE-31-P (Version 2.0) will be utilized to assess quality of life. The QOLIE-31-P 
assessment must be completed by the patients. Patients who are cognitively impaired and 
cannot complete the QOLIE-31-P assessment may still participate in the study, by 
obtaining a waiver for QOLIE-31-P completion from the study medical monitor. 
 
4 
STATISTICAL METHODS 
4.1 
Study Patients 
4.1.1 Disposition of Patients 
Patients are free to discontinue their participation in the study at any time and without 
prejudice to further treatment at their local site. The Investigator must withdraw any 
patient from the study if that patient requests to be withdrawn. Patients withdrawn from 
the study will not be replaced, regardless of the reason for withdrawal. The patient’s 
participation in this study may be discontinued due to the following reasons: 
 
• Patient experiences an intolerable AE. 
• Investigator decides patient has an “unsatisfactory response – efficacy.” 
• Patient becomes pregnant. 
• Patient is unwilling or unable to continue the study. 
• Patient is non-compliant with study procedures. 
• Patient needs medication not allowed in the protocol. 
• Any clinically significant change in patient’s medical condition. 
• Persistent ALT or aspartate aminotransferase (AST) above 3 times the ULN; will 
be confirmed by repeating laboratory assessment within 1 week. 
• ALT or AST levels are above 5 times the ULN at any time during the study. 
• Confirmed QTc prolongation defined as QTc (Bazett’s) >500 msec or an increase 
in QTc (Bazett’s) of >60 msec from baseline. 
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• Investigator decides that withdrawal from the study is in the best interest of the 
patient. 
• Request of the Sponsor. 
• Hematological reasons or infections – for all such patients, the investigator shall 
report these in an expedited manner, whether or not they are considered serious or 
unexpected. 
 
A summary of the number and percentage of discontinuations by primary reason will be 
provided together with descriptive statistics for the time until treatment discontinuation 
(days). 
 
A by-patient listing of patient withdrawal/study completion details will also be provided. 
 
4.1.2 Analysis Populations 
The Safety Population is defined as all patients who successfully completed the transition 
phase of Study VRX-RET-E22-302 and were enrolled into the long-term study VRX-
RET-E22-304.   The Transition phase is the phase of Study VRX-RET-E22-302 during 
which patients were adjusted to a 300 mg TID dose.  
 
There will be no other population for this study. 
 
 
4.2 
Demographic and Other Baseline Characteristics 
Demographic and baseline characteristics were not collected as part of the VRX-RET-
E22-304 case report form (CRF).  For the following summaries of demographic and other 
baseline characteristics, unless otherwise noted, the last recorded value prior to 
commencement of study treatment in the VRX-RET-E22-302 study will be used as 
baseline.   
 
A summary of the following demographic variables will be presented at baseline: 
 
• age 
• sex 
• race 
• weight 
• height 
• body mass index (BMI)  
• duration of partial and generalized seizures, separately 
• type of onset of partial and generalized seizures, separately 
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• Baseline seizure type cohorts 
• number of background AEDs  
• number of patients using Vagal Nerve Stimulators 
• CGI severity baseline scores 
 
A patient’s age in years will be calculated as the number of completed years between the 
date of the informed consent for the VRX-RET-E22-302 study and date of birth (i.e. date 
of informed consent minus date of birth divided by 365.25).  Age, weight and BMI will 
be summarized using continuous descriptive statistics. The number and percentage of 
patients in each sex category (male and female), and each race category (Caucasian, 
African-American, Hispanic, Asian and Other), will be reported using categorical 
descriptive statistics. 
 
Duration of partial and generalized epilepsy is defined as the difference between Year of 
Onset recorded in Epilepsy History and year of Visit 1 (screening) for the VRX-RET-
E22-302 study. The duration of partial epilepsy will be summarized using continuous 
descriptive statistics.   
 
By-patient listings of all demographic data and baseline characteristics will also be 
provided. 
 
 
4.3 
General Considerations 
Study day is defined as the number of days relative to Day 0 (i.e., the start of study 
treatment in the double-blind study VRX-RET-E22-302), computed as (the date – Day 0 
date+1).   
 
Continuous data that are assumed to be normally distributed will be summarized in terms 
of the mean, standard deviation (SD), median, minimum, maximum and number of 
observations. Continuous data that are expected to be skewed will be presented in terms 
of the maximum, upper quartile, median, lower quartile, minimum and number of 
observations.  The minimum and maximum will be reported to the same number of 
decimal places as the raw data recorded in the database.  The mean, SD, median, lower 
quartile and upper quartile will be reported to one more decimal place than the raw data 
recorded in the database.  In general, the maximum number of decimal places reported 
shall be four for any summary statistic. 
 
Categorical data will be summarized in terms of the number of patients providing data at 
the relevant time point (n), frequency counts and percentages.  Percentages will be 
presented to one decimal place. Percentages will not be presented for zero counts.  
Percentages will be calculated using n as the denominator.  
 
 
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4.4 
Efficacy Evaluation 
“Monthly total partial seizure” as well as "monthly total seizure" rates will be calculated 
for the entire open-label part of Study VRX-RET-E22-304 and statistically described. 
“Monthly total partial seizure” rate is defined as the sum of total partial seizures 
throughout the open-label portion (of Study VRX-RET-E22-304), divided by open-label 
duration in days, standardized by 28 days (1 month). “Monthly total seizure” rate is 
defined as the sum of partial and generalized (or unclassified) seizures throughout the 
open-label duration in days, standardized by 28 days (1 month). 
 
Monthly total partial seizure rates observed during the open-label extension period will 
be compared to the monthly total seizure rates observed during the Baseline phase of the 
double-blind study VRX-RET-E22-302. The baseline monthly total seizure rates will 
only be derived for patients who enter this open-label extension and have a monthly total 
partial seizure rate during the open-label extension period.  The percent change in 
monthly total partial seizure rates from the Baseline phase will be classified into <0, [0, 
25), [25, 50), [50, 75), [75, 100] with a description of the frequencies.  The responder rate 
during the open-label study (defined as a reduction in seizure frequency ≥50%) will also 
be summarized using descriptive statistics. 
 
The monthly total partial seizure rates compared to the baseline monthly total partial 
seizure rate will be presented cumulatively for each timepoint (months 1, 3, 6, 9, 12, 16, 
20, 24, 28, 32 and 36) during the open label extension period and separately for eleven 
cohorts of patients treated with retigabine for at least 1, 3, 6, 9, 12, 16, 20, 24, 28, 32 and 
36 months.   In each cohort, patients will be followed for entire indicated duration of 
treatment.  For example, patients in the 36-month cohort will also be part of the shorter-
duration cohorts. 
 
A similar analysis will be repeated for the responder rate during the open-label study. 
 
A plot of the median percent reduction from baseline in seizure frequency over time by 
duration of treatment will also be produced. 
 
The number of seizure free days, in percent to the individual duration of the open-label 
treatment, will be calculated and summarized using descriptive statistics. “Percent seizure 
free days” is defined as the number of days without any seizures (partial or generalized) 
divided by open-label duration in days, in percent. This percentage will be classified into 
[0, 25), [25, 50), [50, 75), [75, 95), [95,100), [=100] and described statistically. The most 
upper class represents completely seizure free patients, the next class almost seizure free 
patients. 
 
Additionally, the proportion of subjects who become seizure free for 6 and 12 month 
rolling intervals will also be determined.  That is, a subject who becomes seizure free for 
any 6 month period of time will qualify for the 6 month metric.  A subject who becomes 
seizure free for any 12 month period of time will qualify for both the 6 month and 12 
month metric.       
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4.5 
Safety Evaluation 
4.5.1 Extent of Exposure 
Exposure Daily Dose is defined as the mean value of daily dosages of study drug, that is 
total dosage taken by a patient divided by number of days the patient participated in the 
study.  The total dosage is defined as sum of the recorded doses in the Study Medication 
and Dose Change Log for each visit.  The number of days patient participated in this 
study is defined as the period from the first dose date (Day 0) to the last recorded dose 
date.   Descriptive statistics of the exposure daily dose of this study will be presented.  
 
Extent of exposure is defined as the total number of days a patient is exposed to study 
drug.  In calculation, the extent of exposure equals the total number of days from the first 
dose date (Day 0) to the last recorded dose date.  If a patient is lost to follow-up, but the 
drug accountability log confirms that the patient has taken study drug, the last visit date 
of the treatment period will be used for calculation of extent of exposure.  For better 
description, extent of exposure (in weeks) will also be categorized (≤ 1, (1-3], (3-6], (6-
9], (9-12], (12-16], (16-20], (20-24], (24-28], (28-32], (32-36], >36).  Descriptive 
statistics for extent of exposure categorized by weeks will additionally be presented.  
 
A by-patient listing of detailed exposure daily dose, dose modifications and extent of 
exposure to study drug will be provided.  Any extreme values for both the exposure daily 
dose and the extent of exposure to study medications will be reported in the listings, in 
case that happens. 
 
 
4.5.2 Adverse Events 
Adverse events (AEs) are monitored from the start of this extension study (informed 
consent provided by patient at the Baseline visit) until 30 days after administration of the 
last dose of study drug (end of study drug taper-off). 
 
The AEs will be coded using the most recent Medical Dictionary for Regulatory 
Activities (MedDRA), Version 9.1. The number and percentage of patients experiencing 
at least one adverse event will be summarized overall and by body system and preferred 
term. In any given body system or preferred term patients will only be counted once. 
Adverse events will further be categorized and summarized by severity and study drug 
relationship. If the same event for a patient has two different severities, the worst will be 
taken. 
 
Abnormal laboratory values do not themselves represent adverse events unless they: 
 
- 
are indicative of a disease or defect, e.g. reduced hematocrit resulting in anemia; 
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- 
necessitate intervention, e.g., administration of packed red blood cells or other 
therapies; and 
- 
result in dose reduction or permanent discontinuation of the drug product. 
 
Worsening of seizure frequency will not be considered an AE but will be captured in the 
efficacy analysis. Those patients who discontinue their treatment prematurely either 
during the double-blind period or choose not to enter the open-label extension study 
should be tapered off their study treatment gradually and will be closely monitored by 
scheduled clinic visits for worsening of their seizure frequency during this period.   
 
Adverse events will be graded for intensity.  An intensity category of mild, moderate, or 
severe, is defined as 
 
Mild 
Causing no limitation of usual activities; the patient may experience 
slight discomfort 
Moderate 
Causing some limitation of usual activities; the patient may experience 
annoying discomfort 
Severe 
Causing inability to carry out usual activities; the patient may 
experience intolerable discomfort or pain. 
 
Adverse events will also be graded, by the investigator, for relationship of the AE to 
study drug.  A relationship to study drug category of not related, possible, probable, 
definite, is defined as 
 
Not Related No temporal association and other etiologies are likely the cause 
Possible 
Temporal association, but other etiologies are likely the cause. 
However, involvement of the study drug cannot be excluded. 
Probable 
Temporal association, other etiologies are possible but unlikely. The 
event may respond if the study drug is discontinued. 
Definite 
Established temporal association with administration of the study drug 
with no other probable cause.  The event should resolve when the study 
drug is discontinued and recur on re-challenge. 
 
The intensity and relationship assessments to study drug are recorded on the AE CRF 
page. 
 
Treatment-emergent AEs (TEAEs) will be tabulated, i.e., those events which are not 
present at baseline or worsened in severity following the start of treatment.  Any adverse 
events starting more than 30 days after the last administration of study drug will not be 
tabulated. 
 
The onset date of an adverse event will be compared to the date of first dose of study 
medication in this extension study to determine if the adverse event is treatment emergent 
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or not.  Adverse events with an onset date on or after the date of first dose of study 
medication will be classified as treatment emergent. 
 
The following adverse event summaries will be provided: 
 
• 
A summary of the number and percentage of patients reporting a treatment emergent 
adverse event by body system, and preferred term 
• 
A summary of the number and percentage of patients reporting a treatment emergent 
adverse event by maximum intensity, body system and preferred term 
• 
A summary of the number and percentage of patients reporting a treatment emergent 
adverse event by relationship to study drug, body system and preferred term 
• 
A summary of the number and percentage of patients reporting a treatment emergent 
adverse event leading to dose modification by  body system and preferred term 
 
For each patient and each adverse event, the worst severity recorded will be attributed 
and used in the by-severity summaries.  Similarly, the worst causality (most related to 
treatment) will be attributed and used in the by-causality summaries.  If severity or 
causality are missing, the worst case will be assumed. 
 
 
The date the AE started should be well collected in CRF data. However, in the unlikely 
case that the AE start date is missing, the AE date will imputed be as follows. 
 
Scenarios 
Day 
Month 
Year 
Imputed AE Onset Date 
 
missing 
 
 
If the month and year of the AE are the 
same as the month and year of the first 
dose date in the extension, use the day of 
the first dose date.  
 
Otherwise use 1 for day.  
 
missing 
 
If year of onset of AE is before the year of 
first dose in the extension, use DEC. 
 
If the year of the AE is the same as the 
year of the first dose date in the extension 
and the day of the AE is greater or equal 
to the day of the first dose in the 
extension, use the month from the first 
dose date.  If the day of the AE is less 
than the day of the first dose in the 
extension, use the month of first dose + 1.  
If the month of the first dose in the 
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extension is DEC, then use month of first 
dose. 
 
If the year of onset of AE is after the year 
of first dose in the extension, use JAN.  
 
 
missing
If the day and month of the AE is before 
the day and month of the first dose in the 
extension, assign the missing year as the 
year of the first dose date + 1.  Otherwise, 
assign the missing year as the year of the 
first dose date.  
missing 
missing 
 
If year of onset of AE is before the year of 
first 
dose 
in 
the 
extension, 
use 
01/07/yyyy. 
 
If the year of the AE is the same as the 
year of the first dose in the extension, use 
the first dose date.   
 
If year of onset of AE is after the year of 
first 
dose 
in 
the 
extension, 
use 
01/01/yyyy. 
 
missing 
missing
If the day of the AE is before the day of 
the first dose in the extension, assign the 
missing month as the month of the first 
dose date + 1 and the year as the year of 
the first dose date.  If the month of the 
first dose in the extension is DEC, then +1 
year and use JAN. 
 
If the day of the AE is on or after the date 
of the first dose in the extension, assign 
the missing month and year as the month 
and year of the first dose date. 
missing 
 
missing
If the month of the AE is the same or after 
the month of the first dose in the 
extension, then use the day and year from 
first dose.   
 
Otherwise, impute the missing day as 1 
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and assign the year of the first dose + 1.  
missing 
missing 
missing
Use the first dose date in the extension. 
   
A by-patient listing of all adverse events (including non-treatment-emergent events) will 
be provided.  This listing will be presented by treatment group and will include: centre, 
patient identifier, age, sex, race, adverse event (body system, preferred term, reported 
term), date of onset, date of resolution, duration, severity, seriousness, action taken, 
outcome and causality.    
 
 
4.5.3 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
A serious adverse event (SAE) is any AE occurring at any dose that results in any of the 
following outcomes: 
• Death 
• Is a life-threatening experience.  Life-threatening means that the patient was, in 
the view of the investigator, at immediate risk of death from the event as it 
occurred 
• Requires in-patient hospitalization or prolongation of existing hospitalization.  
Hospitalization for elective treatment or a pre-existing condition that did not 
worsen during the clinical investigation is not considered an AE. 
• Results in a persistent or significant disability/incapacity (i.e., a substantial 
disruption of a person’s ability to conduct normal life functions).  Disability is 
defined as a substantial disruption in a person’s ability to conduct normal life 
functions 
• Results in a congenital anomaly/birth defect 
Important medical events that may not result in death, be life threatening, or require 
hospitalization may be considered SAEs only when they jeopardize the health of the 
patient or require medical or surgical intervention to prevent one of the outcomes listed in 
the above definition.  If there is any doubt whether the information constitutes an SAE, 
the information is treated as an SAE in this study. 
 
The following adverse event summaries will be provided: 
 
• 
A summary of the number and percentage of patients reporting a fatal treatment 
emergent  adverse event by body system, and preferred term  
• 
A summary of the number and percentage of patients reporting a serious treatment 
emergent adverse event by body system, and preferred term  
• 
A summary of the number and percentage of patients reporting a treatment emergent 
adverse event leading to withdrawal from the study by  body system and preferred 
term 
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The following adverse event listings will also be provided: 
 
• 
A by-patient listing of all deaths that occurred during the study 
• 
A by-patient listing of all serious adverse events 
• 
A by-patient listing of all adverse events leading to withdrawal 
 
 
4.5.4 Clinical Laboratory Evaluation 
All clinical laboratory assessments are implemented by a central laboratory.   
 
The clinical laboratory data were collected at baseline, Months 1, 3, 6, 9, 12, 16, 20, 24, 
28, 32, and 36.  Additional hematological assessments are collected at Months 2, 4, 8 and 
10.   
 
The laboratory data include: 
 
1. Hematology: hemoglobin, hematocrit, RBC count, WBC count with differential, 
and platelet count. 
2. Blood chemistries: sodium, potassium, chloride, bicarbonate, glucose, cholesterol, 
creatinine, calcium, phosphorus, BUN, uric acid, total bilirubin, total protein, AST, 
ALT, and alkaline phosphatase levels.  
3. Routine urinalysis: specific gravity, pH, protein/albumin, glucose/sugar, 
ketones/acetone, and hemoglobin/blood.  In order to standardize measurements, 
Bayer multistix 8-SG or equivalent dipsticks will be used.  
4. Microscopic urinalysis: RBC, WBC, casts, and crystals/cells. 
 
Descriptive statistics for laboratory results and change from baseline for each visit will be 
presented separately for hematology, biochemistry and urinalysis parameters. The 
number of patients with clinically significant liver function tests will also be presented. 
 
A by-patient listing of all laboratory data will also be provided with abnormal values 
highlighted, and including centre, patient identifier, age, sex, race, weight and visit.   A 
listing of the central laboratory reference ranges will also be provided. 
 
 
4.5.5 Vital Signs, Physical Findings and Other Observations Related to Safety 
4.5.5.1 Vital Sign Measurements 
 
Vital sign measurements, including supine and standing  measurements of systolic blood 
pressure (mmHg), diastolic blood pressure (mmHg), pulse (bpm), weight (kg), and oral 
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temperature (°C), are collected at each visit during the open-label extension with the 
exception of the haematological evaluation visits (Months 2, 4, 8 and 10).  
 
Descriptive statistics for vital sign results and change from baseline for each visit will be 
presented.  
 
The number of patients with orthostatic hypotension will also be presented.  Orthostatic 
hypotension is defined as either a systolic blood pressure decrease of ≥20 mmHg upon 
standing or a diastolic blood pressure decrease of ≥10 mmHg upon standing.  
 
A by-patient listing of all vital sign measurements will also be provided. 
 
4.5.5.2 ECG 
 
The ECG parameters assessment includes heart rate, PR interval, QRS interval, QT 
interval, and QTc interval.   
 
QT intervals will be corrected using both Bazett’s and Fridericia’s formulas.  For 
purposes of data analysis, Fridericia’s QT correction will be considered as primary.  The 
QT interval and QTc interval data will be presented both as analysis of central tendency 
(e.g. means, medians) and categorical analyses.   
 
Categorical analysis of QT/QTc interval data are based on the number and percentage of 
patients meeting or exceeding the limit value that is defined in ICH guideline E14 [1], i.e. 
Absolute QTc interval prolongation if QTc interval >450, >480, or >500 msec and 
Change from baseline in QTc interval >30 or >60 msec.   
 
A listing of patients meeting or exceeding the highest limit value, i.e. QTc interval >500 
msec or change from baseline in QTc interval >60 msec, will be provided. The listing of 
patients will include the dose of study medications that the patient was taking on the day 
prior to the ECG reading.  
 
Descriptive statistics for QT/QTc intervals will be first presented in the tables. The 
number and percentage of patients for the QT/QTc category in ICH guideline E14 will be 
presented in the tables, and the patients who have significant QT/QTc measures will be 
provided in the listings.  The means and standard deviations of QT/QTc intervals by 
week and the patient with significant QT/QTc changes will be also presented in the 
tables.  
 
A by-patient listing of all ECG data will also be provided. 
 
4.5.5.3 Physical and Neurological Examination 
 
A complete physical examination and complete neurological examination was performed 
at baseline and at Months 12, 24, and 36.  Brief neurological examinations were also 
performed at all other visits during the open-label extension.   
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For the 15 items of complete physical exam and 42 items of complete neurological exam, 
the number and percentage of patients with normal or abnormal results will be presented. 
 
A by-patient listing of physical and neurological examination data will also be provided. 
 
4.5.5.4 AUA Symptom Index 
 
An AUA Symptoms Index, a 7-item Likert-scored scale describing urinary bladder 
function, is completed by the investigator at the baseline phase, and at Months 1, 3 and 
12.  
Descriptive statistics (n, mean, std, median, minimum, maximum) of the AUA symptom 
index scores in each treatment group will be presented by two table layouts: 1) AUA raw 
overall scores at baseline, Months 1, 3 and 12, 2) change from baseline to Month 1, 2 and 
12.  
Besides the descriptive statistics tables, AUA symptom index scores will be categorized 
by using 3 levels: 0-7 as mild, 8-19 as moderate, and >19 as severe. A shift table of the 
number (%) of patients in the categories of mild, moderate, and severe will be provided.  
A listing of AUA symptom index data will be provided. 
 
4.5.5.5 Post-void Residual (PVR) Bladder Ultrasound 
 
PVR bladder ultrasound data are collected at baseline, and at Months 1, 3 and 12 to 
assess the patient’s bladder function.  
 
Descriptive statistics for the PVR bladder ultrasound results and change from baseline at 
each visit will be presented. The number and percentage of patients with abnormal PVR 
bladder ultrasound at each visit will also be presented. 
  
In addition, PVR bladder ultrasound scores will be categorized by using 3 levels: >50ml, 
>100ml and >150ml will also be provided.  
A by-patient listing of the PVR Bladder Ultrasound data will also be provided. 
 
 
4.5.6 Concomitant Medications 
Any on-going medications, including prescription and non-prescription as well as 
vitamins and herbal supplements, and any new medications taken during the study should 
be recorded on the Concomitant Medication Record form.  The concomitant medications 
will be coded according to the World Health Organization (WHO) Drug Dictionary.  The 
number and percentage of concomitant medications will be summarized in tables.   
 
A by-patient listing of all concomitant medications will also be provided. 
 
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4.6 
Quality of Life in Epilepsy (QOLIE-31-P) 
The patient-weighted 31-item questionnaire (QOLIE-31-P, version 2.0) was administered 
in this study, describing health-related quality of life in people with epilepsy.  The 
QOLIE-31-P form will be completed by the patient at baseline phase and at Months 3, 6, 
9, 12, 24, and 36. Subscale and total scores will be calculated and the subscales grouped 
into two factors: emotional/psychological effects (seizure worry, overall QOL, emotional 
well-being, energy/fatigue subscales) and medical/social effects (medication effects, 
work-driving-social limits, cognitive function subscales). 
 
Descriptive statistics of the QOLIE-31-P data will be presented in the tables and listings 
for 
• Overall assessment 
• Emotional/Psychological Effects domain 
• Medical/Social Effects domain. 
 
 
4.7 
Determination of Sample Size 
All participants who have successfully completed the Maintenance and Transition phases 
of Study VRX-RET-E22-302, for the treatment of partial-onset seizures are eligible (up 
to approximately 510 patients). 
 
 
4.8 
Changes in the Conduct of the Study or Planned Analysis 
No changes in the conduct of the study or planned analysis have occurred. 
 
 
5 
REFERENCES 
 [1] ICH Steering Committee, “The Clinical Evaluation of QT/QTc Interval Prolongation 
and Proarrhythmic Potential for Non-antiarrythmic Drugs, E14”, 12 May 2005. 
 
 
6 
REPORTING OUTPUT 
All outputs will be produced using SAS® version 9.1.3 or a later version (if available at 
PAREXEL).  The REPORT procedure will be used to produce all tables and listings 
whenever possible.  The GPLOT procedure will be used to produce all figures whenever 
possible.  All statistical appendices (supportive SAS output) will be output directly from 
the appropriate SAS procedure. 
 
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Post-text tables, listings and statistical appendices will be produced as RTF files using 
ODS and Courier New font size 9.  Figures will be produced as RTF files using ODS and 
font=simplex.  For all outputs, the page numbering will be applied to ensure that when 
the RTF files are combined, the page numbering remains fixed. 
 
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7 
LIST OF TABLES 
TABLE 1  NUMBER (%) OF PATIENTS WHO DISCONTINUED TREATMENT 
DURING THERAPY PHASE BY PRIMARY REASON 
TABLE 2  TIME UNTIL TREATMENT DISCONTINUATION (DAYS) 
DESCRIPTIVE STATISTICS 
TABLE 3  DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
TABLE 4  EPILEPSY HISTORY 
TABLE 5  CLINICAL GLOBAL IMPRESSION (CGI) – SEVERITY AT BASELINE 
TABLE 6  NUMBER OF BACKGROUND AEDs AT BASELINE N (%) 
TABLE 7  PRESENCE OF PARTIAL SEIZURE BY SUBTYPE DURING BASELINE 
PERIOD 
TABLE 9.1  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE 
FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 1 MONTH DURING THE OPEN-LABEL EXTENSION 
TABLE 9.2  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE 
FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 3 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 9.3  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE 
FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 6 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 9.4  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE 
FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 9 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 9.5  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE 
FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 12 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 9.6  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE 
FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 16 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 9.7  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE 
FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 20 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 9.8  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE 
FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 24 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 9.9  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE 
FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 28 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 9.10  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE 
FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 32 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 9.11  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE 
FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 36 MONTHS DURING THE OPEN-LABEL EXTENSION 
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Filename: 87272_304_SAP_v2_final 
 
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TABLE 10  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL 
PARTIAL SEIZURE FREQUENCY) 
TABLE 11.1  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL 
PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH 
RETIGABINE FOR AT LEAST 1 MONTH DURING THE OPEN-LABEL 
EXTENSION 
TABLE 11.2  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL 
PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH 
RETIGABINE FOR AT LEAST 3 MONTHS DURING THE OPEN-LABEL 
EXTENSION 
TABLE 11.3  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL 
PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH 
RETIGABINE FOR AT LEAST 6 MONTHS DURING THE OPEN-LABEL 
EXTENSION 
TABLE 11.4  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL 
PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH 
RETIGABINE FOR AT LEAST 9 MONTHS DURING THE OPEN-LABEL 
EXTENSION 
TABLE 11.5  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL 
PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH 
RETIGABINE FOR AT LEAST 12 MONTHS DURING THE OPEN-LABEL 
EXTENSION 
TABLE 11.6  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL 
PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH 
RETIGABINE FOR AT LEAST 16 MONTHS DURING THE OPEN-LABEL 
EXTENSION 
TABLE 11.7  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL 
PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH 
RETIGABINE FOR AT LEAST 20 MONTHS DURING THE OPEN-LABEL 
EXTENSION 
TABLE 11.8  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL 
PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH 
RETIGABINE FOR AT LEAST 24 MONTHS DURING THE OPEN-LABEL 
EXTENSION 
TABLE 11.9  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL 
PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH 
RETIGABINE FOR AT LEAST 28 MONTHS DURING THE OPEN-LABEL 
EXTENSION 
TABLE 11.10  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL 
PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH 
RETIGABINE FOR AT LEAST 32 MONTHS DURING THE OPEN-LABEL 
EXTENSION 
TABLE 11.11  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL 
PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH 
RETIGABINE FOR AT LEAST 36 MONTHS DURING THE OPEN-LABEL 
EXTENSION 
CONFIDENTIAL
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Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
Filename: 87272_304_SAP_v2_final 
 
page 25 of 148 
 
TABLE 12  PROPORTION OF PATIENTS EXPERIENCING A REDUCTION IN 
MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY 
TABLE 13  PROPORTION OF SEIZURE-FREE DAYS 
TABLE 14  EXTENT OF EXPOSURE TO STUDY MEDICATION 
TABLE 15  NUMBER (%) OF PATIENTS REPORTING TREATMENT-EMERGENT 
ADVERSE EVENTS 
TABLE 16  NUMBER (%) OF PATIENTS REPORTING ADVERSE EVENTS BY 
MAXIMUM SEVERITY 
TABLE 17 NUMBER (%) OF PATIENTS REPORTING TREATMENT-EMERGENT 
ADVERSE EVENTS AT LEAST POSSIBLY RELATED TO STUDY DRUG 
TABLE 18 NUMBER (%) OF PATIENTS REPORTING TREATMENT-EMERGENT 
ADVERSE EVENTS THAT LEAD TO DOSE MODIFICATION/INTERRUPTION 
TABLE 19 NUMBER (%) OF PATIENTS REPORTING FATAL TREATMENT-
EMERGENT ADVERSE EVENTS 
TABLE 20 NUMBER (%) OF PATIENTS REPORTING SERIOUS TREATMENT-
EMERGENT ADVERSE EVENTS 
TABLE 21 NUMBER (%) OF PATIENTS REPORTING ADVERSE EVENTS THAT 
CAUSED WITHDRAWAL FROM STUDY 
TABLE 22  OBSERVED MEANS AND STANDARD DEVIATIONS OF 
LABORATORY TEST RESULTS AND CHANGE FROM BASELINE BY 
MONTH - SERUM CHEMISTRY 
TABLE 24 OBSERVED MEANS AND STANDARD DEVIATIONS OF 
LABORATORY TEST RESULTS AND CHANGE FROM BASELINE BY 
MONTH – HEMATOLOGY 
TABLE 25 OBSERVED MEANS AND STANDARD DEVIATIONS OF 
LABORATORY TEST RESULTS AND CHANGE FROM BASELINE BY 
MONTH – URINALYSIS 
TABLE 23  NUMBER (%) OF PATIENTS WITH CLINICALLY SIGNIFICANT 
LIVER FUNCTION TEST RESULTS 
TABLE 26  FREQUENCY DISTRIBUTION OF CATEGORICAL LABORATORY 
TEST RESULTS - URINALYSIS 
TABLE 27  SUMMARY STATISTICS OF ELECTROCARDIOGRAM MEASURES 
TABLE 28  NUMBER (%) OF PATIENTS EXAMINING QTC INTERVAL BY 
CATEGORY 
TABLE 29  NUMBER (%) OF PATIENTS EXAMINING QTC INTERVAL CHANGE 
FROM BASELINE BY CATEGORY 
TABLE 30  OBSERVED MEANS AND STANDARD DEVIATIONS OF QTC 
INTERVALS AND CHANGE FROM BASELINE BY MONTH 
TABLE 31  OBSERVED MEANS AND STANDARD DEVIATIONS OF VITAL SIGN 
RESULTS AND CHANGE FROM BASELINE BY MONTH 
TABLE 33  NUMBER (%) OF PATIENTS WITH ABNORMAL RESULTS OF 
PHYSICAL EXAMINATIONS 
TABLE 34  NUMBER (%) OF PATIENTS WITH ABNORMAL RESULTS OF 
NEUROLOGICAL EXAMINATIONS 
TABLE 35  NUMBER (%) OF PATIENTS WITH ABNORMAL AUA SYMPTOM 
INDEX 
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Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
Filename: 87272_304_SAP_v2_final 
 
page 26 of 148 
 
TABLE 36 DESCRIPTIVE STATISTICS OF RAW OVERALL AUA SCORES 
TABLE 37  NUMBER (%) OF PATIENTS WHO HAD MILD, MODERATE, SEVERE 
AUA SCORES 
TABLE 38  AUA CATEGORY SHIFT FROM BASELINE 
TABLE 39  NUMBER (%) OF PATIENTS WITH ABNORMAL PVR BLADDER 
ULTRASOUND 
TABLE 40  DESCRIPTIVE STATISTICS OF PVR BLADDER ULTRASOUND 
TABLE 41 NUMBER (%) OF PATIENTS WITH A CLINICALLY SIGNIFICANT 
PVR BLADDER ULTRASOUND 
TABLE 42  NUMBER (%) OF PATIENTS TAKING CONCOMITANT 
MEDICATIONS 
TABLE 43  OBSERVED MEANS AND STANDARD DEVIATIONS OF QOL IN 
EPILEPSY (QOLIE-31-P) AND CHANGE FROM BASELINE BY MONTH 
 
 
 
 
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Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
Filename: 87272_304_SAP_v2_final 
 
page 27 of 148 
 
8 
LIST OF FIGURES 
FIGURE 1  MEDIAN PERCENT REDUCTION FROM BASELINE IN SEIZURE 
FREQUENCY OVER TIME BY DURATION OF TREATMENT EXPOSURE 
 
 
 
 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
Filename: 87272_304_SAP_v2_final 
 
page 28 of 148 
 
9 
LIST OF PATIENT DATA LISTINGS 
LISTING 1  PATIENT WITHDRAWAL/STUDY COMPLETION 
LISTING 2  INCLUSION/EXCLUSION CRITERIA/ELIGIBILITY 
LISTING 3  DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
LISTING 4  STUDY MEDICATION COMPLIANCE 
LISTING 5  CONCOMITANT MEDICATIONS EXCLUDING BACKGROUND 
ANTI-EPILEPTIC DRUGS (AEDs) 
LISTING 6  CONCOMITANT TREATMENTS OTHER THAN MEDICATION 
LISTING 7  PARTIAL SEIZURE FREQUENCY 
LISTING 8  GENERALIZED OR UNCLASSIFIED SEIZURE FREQUENCY 
LISTING 9  EXTENT OF EXPOSURE TO STUDY MEDICATION 
LISTING 10  ADVERSE EVENTS CODING DICTIONARY MAPPING 
LISTING 11  ADVERSE EVENTS 
LISTING 12  TREATMENT-EMERGENT ADVERSE EVENTS 
LISTING 13  TREATMENT-EMERGENT ADVERSE EVENTS AT LEAST 
POSSIBLY RELATED TO STUDY MEDICATION 
LISTING 14  TREATMENT-EMERGENT ADVERSE EVENTS THAT CAUSED 
WITHDRAWAL FROM STUDY 
LISTING 15  TREATMENT-EMERGENT ADVERSE EVENTS THAT LEAD TO 
DOSE MODIFICATION/INTERRUPTION 
LISTING 16  DEATHS 
LISTING 17  SERIOUS TREATMENT-EMERGENT ADVERSE EVENTS 
LISTING 18  LABORATORY REFERENCE RANGES 
LISTING 19  HEMATOLOGY LABORATORY TEST RESULTS 
LISTING 20  BLOOD SERUM CHEMISTRY LABORATORY TEST RESULTS 
LISTING 21  URINALYSIS LABORATORY TEST RESULTS 
LISTING 22 ECG DIAGNOSIS/COMMENTS INFORMATION 
LISTING 23  ECG RESULTS 
LISTING 24  ECGS NOT PERFORMED AND THEIR REASON FOR NOT 
PERFORMING 
LISTING 25 ECG RESULTS FOR PATIENTS WITH QTC INTERVAL 
>500MSEC OR CHANGE FROM BASELINE IN QTC INTERVAL >60MSEC 
LISTING 26  VITAL SIGNS 
LISTING 27  ABNORMAL PHYSICAL EXAMINATION RESULTS 
LISTING 28 ABNORMAL NEUROLOGICAL EXAMINATION RESULTS 
LISTING 29  AUA SYMPTOM INDEX 
LISTING 30  PVR BLADDER ULTRASOUND RESULTS 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
Filename: 87272_304_SAP_v2_final 
 
page 29 of 148 
 
LISTING 31  QUALITY OF LIFE IN EPILEPSY SCORES (QOLIE-31-P) 
 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
Filename: 87272_304_SAP_v2_final 
 
page 30 of 148 
 
 
10 TABLE SHELLS 
 
 
 
CONFIDENTIAL
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Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 31 of 148 
 
 
TABLE 1  NUMBER (%) OF PATIENTS WHO DISCONTINUED TREATMENT DURING THERAPY PHASE BY PRIMARY REASON 
SAFETY POPULATION 
 
 
RETIGABINE 
 (N=XXX) 
 
 
DISCONTINUED ANY REASON 
xx (xx.x%) 
 
 
ADVERSE EVENT 
xx (xx.x%) 
UNSATISFACTORY RESPONSE – EFFICACY 
xx (xx.x%) 
PREGNANT 
xx (xx.x%) 
UNWILLING OR UNABLE TO CONTINUE THE STUDY 
xx (xx.x%) 
NON-COMPLIANT WITH STUDY PROCEDURES 
xx (xx.x%) 
REQUIRES MEDICATION NOT ALLOWED IN THE PROTOCOL 
xx (xx.x%) 
CLINICALLY SIGNIFICANT CHANGE IN MEDICAL CONDITION 
xx (xx.x%) 
PERSISTENT ALT OR AST ABOVE 3xULN 
xx (xx.x%) 
ALT OR AST ABOVE 5xULN AT ANY TIME 
xx (xx.x%) 
CONFIRMED QTC PROLONGATION 
xx (xx.x%) 
INVESTIGATOR DECISION 
xx (xx.x%) 
SPONSOR REQUEST 
xx (xx.x%) 
FAILURE TO RETURN 
xx (xx.x%) 
PATIENT REQUEST UNRELATED TO STUDY 
xx (xx.x%) 
OTHER EVENT 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 32 of 148 
 
 
 
TABLE 2  TIME UNTIL TREATMENT DISCONTINUATION (DAYS) DESCRIPTIVE STATISTICS 
SAFETY POPULATION 
 
 
STATISTICS 
RETIGABINE 
 (N=XXX) 
 
 
N 
xxx 
MEAN 
xxx.x 
STD 
xxx.xx 
MEDIAN 
xxx.x 
MININUM 
xxx 
MAXIMUM 
xxx 
 
 
 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 33 of 148 
 
 
 
TABLE 3  DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
SAFETY POPULATION 
 
 
STATISTICS 
RETIGABINE 
 (N=XXX) 
 
 
AGE - YEAR 
 
N 
xxx 
MEAN 
xxx.x 
STD 
xxx.xx 
MEDIAN 
xxx.x 
MININUM 
xxx 
MAXIMUM 
xxx 
 
 
SEX - N (%) 
 
MALE 
xxx (xx.x%) 
FEMALE 
xxx (xx.x%) 
 
 
RACE - N (%) 
 
CAUCASIAN 
xxx (xx.x%) 
AFRICAN-AMERICAN (BLACK) 
xxx (xx.x%) 
HISPANIC 
xxx (xx.x%) 
ASIAN 
xxx (xx.x%) 
OTHER 
xxx (xx.x%) 
 
 
HEIGHT – CM 
 
N 
xxx 
MEAN 
xxx.x 
STD 
xxx.xx 
MEDIAN 
xxx.x 
MININUM 
xxx 
MAXIMUM 
xxx 
 
 
WEIGHT – KG 
 
N 
xxx 
MEAN 
xxx.x 
STD 
xxx.xx 
MEDIAN 
xxx.x 
MININUM 
xxx 
MAXIMUM 
xxx 
 
 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 34 of 148 
 
 
 
TABLE 3  DEMOGRAPHIC AND BASELINE CHARACTERISTICS 
SAFETY POPULATION 
 
 
 
 
 
STATISTICS 
RETIGABINE 
(N=XXX) 
 
 
BMI – (KG/M^2) 
 
N 
xxx 
MEAN 
xxx.x 
STD 
xxx.xx 
MEDIAN 
xxx.x 
MININUM 
xxx 
MAXIMUM 
xxx 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 35 of 148 
 
 
TABLE 4  EPILEPSY HISTORY 
SAFETY POPULATION 
 
TYPE OF EPILEPSY 
 
STATISTICS 
RETIGABINE 
 (N=XXX) 
 
 
PARTIAL (PRIMARY DIAGNOSIS) 
 
 
 
 
DURATION – YEARS 
 
 
N 
xxx 
 
MEAN 
xxx.x 
 
STD 
xxx.xx 
 
MEDIAN 
xxx.x 
 
MININUM 
xxx 
 
MAXIMUM 
xxx 
 
 
GENERALISED 
 
 
 
 
DURATION – YEARS 
 
 
N 
xxx 
 
MEAN 
xxx.x 
 
STD 
xxx.xx 
 
MEDIAN 
xxx.x 
 
MININUM 
xxx 
 
MAXIMUM 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 36 of 148 
 
 
 
 
 
 
FOOTNOTES: 
A PATIENT CAN HAVE EPILESPY HISTORY RECORDED FOR EACH TYPE OF EPILEPSY. 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 37 of 148 
 
 
TABLE 5  CLINICAL GLOBAL IMPRESSION (CGI) – SEVERITY AT BASELINE 
SAFETY POPULATION 
 
 
STATISTICS 
RETIGABINE 
 (N=XXX) 
 
 
CGI-SEVERITY  
 
 
N 
xxx 
 
MEAN 
xxx.x 
 
STD 
xxx.xx 
 
MEDIAN 
xxx.x 
 
MININUM 
xxx 
 
MAXIMUM 
xxx 
 
 
CGI-SEVERITY 
 
 
AMONG THE MOST EXTREMELY SEVERE 
xxx (xx.x%) 
 
VERY SEVERE 
xxx (xx.x%) 
 
MARKED SEVERITY 
xxx (xx.x%) 
 
MODERATE SEVERITY 
xxx (xx.x%) 
 
MILD SEVERITY 
xxx (xx.x%) 
 
VERY MILD SEVERITY 
xxx (xx.x%) 
 
NO SEIZURES 
xxx (xx.x%) 
 
NOT ASSESSED 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
   
 
 
   
 
 
 
   
 
 
 
   
 
 
 
   
 
 
 
   
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 38 of 148 
 
 
 
TABLE 6  NUMBER OF BACKGROUND AEDs AT BASELINE N (%) 
SAFETY POPULATION 
 
 
CATEGORY 
RETIGABINE 
 (N=XXX) 
 
 
NUMBER OF AEDs  
 
 
1 
xxx (xx.x%) 
 
2 
xxx (xx.x%) 
 
3 
xxx (xx.x%) 
 
 
VAGAL NERVE STIMULATOR USED? 
 
 
YES 
xxx (xx.x%) 
 
NO 
xxx (xx.x%) 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 39 of 148 
 
 
TABLE 7  PRESENCE OF PARTIAL SEIZURE BY SUBTYPE DURING BASELINE PERIOD 
SAFETY POPULATION 
 
 
CATEGORY 
RETIGABINE 
 (N=XXX) 
 
 
BASELINE PERIOD 
 
 N 
xxx 
 SIMPLE PARTIAL SEIZURES WITH MOTOR SIGNS 
xxx (xx.x%) 
 SIMPLE PARTIAL SEIZURES WITHOUT MOTOR SIGNS 
xxx (xx.x%) 
 SIMPLE PARTIAL SEIZURES WITH AND WITHOUT MOTOR SIGNS 
xxx (xx.x%) 
 COMPLEX PARTIAL SEIZURES 
xxx (xx.x%) 
 PARTIAL SEIZURES EVOLVING TO SECONDARY GENERALISED 
xxx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 40 of 148 
 
 
 
 
 
FOOTNOTES: A PATIENT CAN APPEAR IN MULTIPLE CATEGORIES. 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 41 of 148 
 
 
TABLE 8  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY 
SAFETY POPULATION 
 
RETIGABINE 
(N=XXX) 
 
 
 
STATISTICS 
 
OBSERVED 
CHANGE FROM 
BASELINE 
PERCENTAGE CHANGE 
FROM BASELINE 
 
 
 
 
BASELINE [1] 
 
 
 
N 
xxx 
 
 
MEAN 
xxx.x 
 
 
STD 
xxx.xx 
 
 
MEDIAN 
xxx.x 
 
 
MININUM 
xxx 
 
 
MAXIMUM 
xxx 
 
 
 
 
 
 
OPEN-LABEL PHASE 
 
 
 
N 
xxx 
xxx 
xxx 
MEAN 
xxx.x 
xxx.x 
xxx.x 
STD 
xxx.xx 
xxx.xx 
xxx.xx 
MEDIAN 
xxx.x 
xxx.x 
xxx.x 
MININUM 
xxx 
xxx 
xxx 
MAXIMUM 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 42 of 148 
 
 
 
FOOTNOTE: 
[1] BASELINE PHASE IN STUDY VRX-RET-E22-302 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 43 of 148 
 
 
TABLE 9.1  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT LEAST 1 MONTH 
DURING THE OPEN-LABEL EXTENSION  
SAFETY POPULATION 
 
RETIGABINE 
(N=XXX) 
 
 
 
STATISTICS 
 
OBSERVED 
CHANGE FROM 
BASELINE 
PERCENTAGE CHANGE 
FROM BASELINE 
 
 
 
 
BASELINE [1] 
 
 
 
 N 
xxx 
 
 
 MEAN 
xxx.x 
 
 
 STD 
xxx.xx 
 
 
 MEDIAN 
xxx.x 
 
 
 MININUM 
xxx 
 
 
 MAXIMUM 
xxx 
 
 
 
 
 
 
MONTH 1 
 
 
 
 N 
xxx 
xxx 
xxx 
 MEAN 
xxx.x 
xxx.x 
xxx.x 
 STD 
xxx.xx 
xxx.xx 
xxx.xx 
 MEDIAN 
xxx.x 
xxx.x 
xxx.x 
 MININUM 
xxx 
xxx 
xxx 
 MAXIMUM 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 44 of 148 
 
 
 
 
FOOTNOTE: [1] BASELINE PHASE IN STUDY VRX-RET-E22-302 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 45 of 148 
 
 
TABLE 9.2  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT LEAST 3 MONTHS 
DURING THE OPEN-LABEL EXTENSION  
SAFETY POPULATION 
 
RETIGABINE 
(N=XXX) 
 
 
 
STATISTICS 
 
OBSERVED 
CHANGE FROM 
BASELINE 
PERCENTAGE CHANGE 
FROM BASELINE 
 
 
 
 
BASELINE [1] 
 
 
 
 N 
xxx 
 
 
 MEAN 
xxx.x 
 
 
 STD 
xxx.xx 
 
 
 MEDIAN 
xxx.x 
 
 
 MININUM 
xxx 
 
 
 MAXIMUM 
xxx 
 
 
 
 
 
 
MONTH 1 
 
 
 
 N 
xxx 
xxx 
xxx 
 MEAN 
xxx.x 
xxx.x 
xxx.x 
 STD 
xxx.xx 
xxx.xx 
xxx.xx 
 MEDIAN 
xxx.x 
xxx.x 
xxx.x 
 MININUM 
xxx 
xxx 
xxx 
 MAXIMUM 
xxx 
xxx 
xxx 
 
 
 
 
MONTH 3 
 
 
 
 N 
xxx 
xxx 
xxx 
 MEAN 
xxx.x 
xxx.x 
xxx.x 
 STD 
xxx.xx 
xxx.xx 
xxx.xx 
 MEDIAN 
xxx.x 
xxx.x 
xxx.x 
 MININUM 
xxx 
xxx 
xxx 
 MAXIMUM 
xxx 
xxx 
xxx 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 46 of 148 
 
 
 
FOOTNOTE: [1] BASELINE PHASE IN STUDY VRX-RET-E22-302 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 47 of 148 
 
 
Use Template for TABLE 9.2 to produce: 
 
TABLE 9.3  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT LEAST 6 MONTHS 
DURING THE OPEN-LABEL EXTENSION 
TABLE 9.4  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT LEAST 9 MONTHS 
DURING THE OPEN-LABEL EXTENSION  
TABLE 9.5  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT LEAST 12 MONTHS 
DURING THE OPEN-LABEL EXTENSION  
TABLE 9.6  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT LEAST 16 MONTHS 
DURING THE OPEN-LABEL EXTENSION  
TABLE 9.7  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT LEAST 20 MONTHS 
DURING THE OPEN-LABEL EXTENSION  
TABLE 9.8  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT LEAST 24 MONTHS 
DURING THE OPEN-LABEL EXTENSION  
TABLE 9.9  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT LEAST 28 MONTHS 
DURING THE OPEN-LABEL EXTENSION  
TABLE 9.10  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT LEAST 32 MONTHS 
DURING THE OPEN-LABEL EXTENSION  
TABLE 9.11  PERCENTAGE CHANGE IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY FOR PATIENTS TREATED WITH RETIGABINE FOR AT LEAST 36 MONTHS 
DURING THE OPEN-LABEL EXTENSION  
 
PROGRAMMING NOTE: EVERY TIMEPOINT SHOULD BE INCLUDED WITHIN THE INDICATED DURATION OF OPEN-LABEL TREATMENT.  E.G. MONTHS 1, 3, 6, 9, 12, 16, 20, 24, 28, 
32 AND 36 WILL BE PRESENTED IN TABLE 9.11. 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 48 of 148 
 
 
TABLE 10  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY) 
SAFETY POPULATION 
 
 
RESPONSE CATEGORY 
RETIGABINE 
 (N=XXX) 
 
 
N 
xx 
RESPONDERS 
xx (xx.x%) 
NON-RESPONDERS 
xx (xx.x%) 
 
 
 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 49 of 148 
 
 
TABLE 11.1  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 1 MONTH DURING THE OPEN-LABEL EXTENSION  
SAFETY POPULATION 
 
 
RESPONSE CATEGORY 
RETIGABINE 
 (N=XXX) 
 
 
MONTH 1 
 
N 
xx 
RESPONDERS 
xx (xx.x%) 
NON-RESPONDERS 
xx (xx.x%) 
 
 
 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 50 of 148 
 
 
TABLE 11.2  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 3 MONTHS DURING THE OPEN-LABEL EXTENSION  
SAFETY POPULATION 
 
 
RESPONSE CATEGORY 
RETIGABINE 
 (N=XXX) 
 
 
MONTH 1 
 
N 
xx 
RESPONDERS 
xx (xx.x%) 
NON-RESPONDERS 
xx (xx.x%) 
 
 
MONTH 3 
 
N 
xx 
RESPONDERS 
xx (xx.x%) 
NON-RESPONDERS 
xx (xx.x%) 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 51 of 148 
 
 
Use Template for TABLE 9.2 to produce: 
 
 
 
TABLE 11.3  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 6 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 11.4  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 9 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 11.5  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 12 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 11.6  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 16 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 11.7  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 20 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 11.8  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 24 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 11.9  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 28 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 11.10  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 32 MONTHS DURING THE OPEN-LABEL EXTENSION 
TABLE 11.11  RESPONDER RATE (>=50% REDUCTION IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY) FOR PATIENTS TREATED WITH RETIGABINE FOR AT 
LEAST 36 MONTHS DURING THE OPEN-LABEL EXTENSION 
 
PROGRAMMING NOTE: EVERY TIMEPOINT SHOULD BE INCLUDED WITHIN THE INDICATED DURATION OF OPEN-LABEL TREATMENT.  E.G. MONTHS 1, 3, 6, 9, 12, 16, 20, 24, 28, 
32 AND 36 WILL BE PRESENTED IN TABLE 11.11. 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 52 of 148 
 
 
TABLE 12  PROPORTION OF PATIENTS EXPERIENCING A REDUCTION IN MONTHLY TOTAL PARTIAL SEIZURE FREQUENCY 
SAFETY POPULATION 
 
 
 
CATEGORY 
RETIGABINE 
 (N=XXX) 
 
 
REDUCTION CATEGORY 
 
[-100%, -75%]  
xx (xx.x%) 
(- 75%, -50%] 
xx (xx.x%) 
(- 50%, -25%] 
xx (xx.x%) 
(- 25%,   0%) 
xx (xx.x%) 
 
 
WITHOUT REDUCTION 
xx (xx.x%) 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 53 of 148 
 
 
TABLE 13  PROPORTION OF SEIZURE-FREE DAYS  
SAFETY POPULATION 
 
 
STATISTICS 
RETIGABINE 
 (N=XXX) 
 
 
SEIZURE-FREE DAYS (%) 
 
N 
xxx 
MEAN 
xxx.x 
STD 
xxx.xx 
MEDIAN 
xxx.x 
MININUM 
xxx 
MAXIMUM 
xxx 
 
 
REDUCTION CATEGORY 
 
SEIZURE-FREE [=100%] 
xx (xx.x%) 
NOT SEIZURE-FREE 
xx (xx.x%) 
[95%, 100%)  
xx (xx.x%) 
[75%,  95%) 
xx (xx.x%) 
[50%,  75%) 
xx (xx.x%) 
[50%,  25%) 
xx (xx.x%) 
[0%,  25%) 
xx (xx.x%) 
 
 
NUMBER OF PATIENTS WHO WERE SEIZURE-FREE FOR 
 
6 MONTHS 
xx (xx.x%) 
12 MONTHS 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 54 of 148 
 
 
 
TABLE 14  EXTENT OF EXPOSURE TO STUDY MEDICATION 
SAFETY POPULATION 
 
 
STATISTICS 
RETIGABINE 
 (N=XXX) 
 
 
EXTENT OF EXPOSURE (DAYS) 
 
N 
xxx 
MEAN 
xxx.x 
STD 
xxx.xx 
MEDIAN 
xxx.x 
MININUM 
xxx 
MAXIMUM 
xxx 
 
 
RETIGABINE EXPOSURE CATEGORY (MONTHS) 
 
N 
xxx (100.0%) 
[0, 1]  
xxx ( xx.x%) 
(1, 3] 
xxx ( xx.x%) 
(3, 6] 
xxx ( xx.x%) 
(6, 9] 
xxx ( xx.x%) 
(9, 12] 
xxx ( xx.x%) 
(12,16] 
xxx ( xx.x%) 
(16,20] 
xxx ( xx.x%) 
(20,24] 
xxx ( xx.x%) 
(24,28] 
xxx ( xx.x%) 
(28,32] 
xxx ( xx.x%) 
(32,36] 
xxx ( xx.x%) 
>36  
 
 
 
DAILY DOSE OF RETIGABINE EXPOSURE (MG) 
 
N 
xxx 
MEAN 
xxx.x 
STD 
xxx.xx 
MEDIAN 
xxx.x 
MININUM 
xxx 
MAXIMUM 
xxx 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 55 of 148 
 
 
 
TABLE 15  NUMBER (%) OF PATIENTS REPORTING TREATMENT-EMERGENT ADVERSE EVENTS 
SAFETY POPULATION 
 
 
SYSTEM ORGAN CLASS 
PREFERRED TERM 
RETIGABINE 
 (N=XXX) 
 
 
ANY ADVERSE EVENT 
xxx ( xx.x%) 
 
 
1ST SYSTEM ORGAN CLASS 
xxx ( xx.x%) 
PREFERRED TERMS BELOW 
xxx ( xx.x%) 
 
 
2ND SYSTEM ORGAN CLASS 
xxx ( xx.x%) 
PREFERRED TERMS BELOW 
xxx ( xx.x%) 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 56 of 148 
 
 
TABLE 16  NUMBER (%) OF PATIENTS REPORTING ADVERSE EVENTS BY MAXIMUM SEVERITY 
SAFETY POPULATION 
 
RETIGABINE 
(N=XXX) 
 
SYSTEM ORGAN CLASS 
PREFERRED TERM 
MILD 
MODERATE 
SEVERE 
 
 
 
 
1ST SYSTEM ORGAN CLASS 
xxx ( xx.x%) 
xxx ( xx.x%) 
xxx ( xx.x%) 
PREFERRED TERMS BELOW 
xxx ( xx.x%) 
xxx ( xx.x%) 
xxx ( xx.x%) 
 
 
 
 
2ND SYSTEM ORGAN CLASS 
xxx ( xx.x%) 
xxx ( xx.x%) 
xxx ( xx.x%) 
PREFERRED TERMS BELOW 
xxx ( xx.x%) 
xxx ( xx.x%) 
xxx ( xx.x%) 
 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 57 of 148 
 
 
Use Template for TABLE 15 to produce: 
 
TABLE 17 NUMBER (%) OF PATIENTS REPORTING TREATMENT-EMERGENT ADVERSE EVENTS AT LEAST POSSIBLY RELATED TO STUDY DRUG 
TABLE 18 NUMBER (%) OF PATIENTS REPORTING TREATMENT-EMERGENT ADVERSE EVENTS THAT LEAD TO DOSE MODIFICATION/INTERRUPTION 
TABLE 19 NUMBER (%) OF PATIENTS REPORTING FATAL TREATMENT-EMERGENT ADVERSE EVENTS 
TABLE 20 NUMBER (%) OF PATIENTS REPORTING SERIOUS TREATMENT-EMERGENT ADVERSE EVENTS 
TABLE 21 NUMBER (%) OF PATIENTS REPORTING ADVERSE EVENTS THAT CAUSED WITHDRAWAL FROM STUDY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 58 of 148 
 
 
TABLE 22  OBSERVED MEANS AND STANDARD DEVIATIONS OF LABORATORY TEST RESULTS AND CHANGE FROM BASELINE BY MONTH - SERUM CHEMISTRY 
SAFETY POPULATION 
 
 
RETIGABINE 
(N=XXX) 
 
 
 
 
TEST NAME (TEST UNIT) 
 
 
 
 
TIMEPOINT 
 
 
n 
 
 
Mean (STD) 
Change from 
Baseline  
Mean (STD) 
 
 
 
 
 
SODIUM (MMOL/L) 
BASELINE 
xxx 
xx.x (xx.xx) 
 
 
MONTH 1 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 3 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 6 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 9 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 12 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 16 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 20 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 24 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 28 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 32 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 36 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
 
 
POTASSIUM (MMOL/L) 
: 
 
 
 
 
 
 
 
 
 
  
 
 
Use Template for TABLE 22 to produce: 
 
TABLE 24 OBSERVED MEANS AND STANDARD DEVIATIONS OF LABORATORY TEST RESULTS AND CHANGE FROM BASELINE BY MONTH – HEMATOLOGY 
TABLE 25 OBSERVED MEANS AND STANDARD DEVIATIONS OF LABORATORY TEST RESULTS AND CHANGE FROM BASELINE BY MONTH – URINALYSIS 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 59 of 148 
 
 
 
 
TABLE 23  NUMBER (%) OF PATIENTS WITH CLINICALLY SIGNIFICANT LIVER FUNCTION TEST RESULTS 
SAFETY POPULATION 
 
 
RETIGABINE (N=XXX) 
 
TEST NAME (TEST 
UNIT) 
 
 
TIMEPOINT 
n 
>3xULN 
>5xULN 
>10xULN 
 
 
 
 
 
 
ALT (MMOL/L) 
BASELINE 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 1 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 3 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 6 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 9 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 12 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 16 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 20 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 24 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 28 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 32 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 36 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
 
 
 
AST (MMOL/L) 
 
 
 
 
 
 
 
 
 
 
 
 
 
REPEAT FOR TOTAL BILIRUBIN AND ALKALINE PHOSPHATASE 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 60 of 148 
 
 
TABLE 26  FREQUENCY DISTRIBUTION OF CATEGORICAL LABORATORY TEST RESULTS - URINALYSIS 
SAFETY POPULATION 
 
 
 
RETIGABINE 
 (N=XXX) 
 
 
TEST NAME 
 
MONTH 1 
 
1+ 
xx (xx.x%) 
2+ 
xx (xx.x%) 
3+ 
xx (xx.x%) 
4+ 
xx (xx.x%) 
 
 
MONTH 3 
 
1+ 
xx (xx.x%) 
2+ 
xx (xx.x%) 
3+ 
xx (xx.x%) 
4+ 
xx (xx.x%) 
 
 
MONTH 6 
 
MONTH 9 
 
MONTH 12 
 
MONTH 16 
 
MONTH 20 
 
MONTH 24 
 
MONTH 28 
 
MONTH 32 
 
MONTH 36 
 
 
 
 
 
REPEAT FOR ALL NON-NUMERIC TEST RESULTS 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 61 of 148 
 
 
 
 
TABLE 27  SUMMARY STATISTICS OF ELECTROCARDIOGRAM MEASURES 
SAFETY POPULATION 
 
 
TIMEPOINT 
EVALUATION – UNIT 
STATISTIC 
RETIGABINE 
 (N=XXX) 
 
 
 
BASELINE AVG 
VENTRICULAR RATE – BPM 
 
 
N 
xxx 
 
MEAN 
xxx.x 
 
STD 
xxx.xx 
 
MEDIAN 
xxx.x 
 
MINIMUM 
xxx 
 
MAXIMUM 
xxx 
 
 
 
 
RR INTERVAL – MS 
 
 
N 
xxx 
 
MEAN 
xxx.x 
 
STD 
xxx.xx 
 
MEDIAN 
xxx.x 
 
MINIMUM 
xxx 
 
MAXIMUM 
xxx 
 
 
 
 
PR INTERVAL – MS 
 
 
N 
xxx 
 
MEAN 
xxx.x 
 
STD 
xxx.xx 
 
MEDIAN 
xxx.x 
 
MINIMUM 
xxx 
 
MAXIMUM 
xxx 
 
 
 
 
QRS INTERVAL – MS 
 
 
N 
xxx 
 
MEAN 
xxx.x 
 
STD 
xxx.xx 
 
MEDIAN 
xxx.x 
 
MINIMUM 
xxx 
 
MAXIMUM 
xxx 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 62 of 148 
 
 
TABLE 27  SUMMARY STATISTICS OF ELECTROCARDIOGRAM MEASURES 
SAFETY POPULATION 
 
 
 
TIMEPOINT 
EVALUATION – UNIT 
STATISTIC 
RETIGABINE 
(N=XXX) 
 
 
 
BASELINE AVG (CONTINUED) 
QT INTERVAL – MS 
 
 
N 
xxx 
 
MEAN 
xxx.x 
 
STD 
xxx.xx 
 
MEDIAN 
xxx.x 
 
MINIMUM 
xxx 
 
MAXIMUM 
xxx 
 
 
 
 
QTc INTERVAL BAZETT – MS 
 
 
N 
xxx 
 
MEAN 
xxx.x 
 
STD 
xxx.xx 
 
MEDIAN 
xxx.x 
 
MINIMUM 
xxx 
 
MAXIMUM 
xxx 
 
 
 
 
QTc INTERVAL FRIDERICIA – MS 
 
 
N 
xxx 
 
MEAN 
xxx.x 
 
STD 
xxx.xx 
 
MEDIAN 
xxx.x 
 
MINIMUM 
xxx 
 
MAXIMUM 
xxx 
 
 
 
 
 
REPEAT FOR TIMEPOINTS MONTH 1, MONTH 3, MONTH 6, MONTH 9, MONTH 12, MONTH 24, MONTH 36 
 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 63 of 148 
 
 
 
TABLE 28  NUMBER (%) OF PATIENTS EXAMINING QTC INTERVAL BY CATEGORY 
SAFETY POPULATION 
 
 
 
TIMEPOINT 
 
CATEGORY 
RETIGABINE 
 (N=XXX) 
 
 
 
BASELINE AVG (CONTINUED) 
ABSOLUTE QTc INTERVAL (MS) 
 
 
FRIDERICIA’S CORRECTION 
 
 
   <= 450 
xx (xx.x%) 
 
(450, 480] 
xx (xx.x%) 
 
(480, 500] 
xx (xx.x%) 
 
    > 500 
xx (xx.x%) 
 
 
 
 
BAZETT’S CORRECTION 
 
 
   <= 450 
xx (xx.x%) 
 
(450, 480] 
xx (xx.x%) 
 
(480, 500] 
xx (xx.x%) 
 
    > 500 
xx (xx.x%) 
 
 
 
 
 
REPEAT FOR TIMEPOINTS MONTH 1, MONTH 3, MONTH 6, MONTH 9, MONTH 12, MONTH 24, MONTH 36 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 64 of 148 
 
 
 
TABLE 29  NUMBER (%) OF PATIENTS EXAMINING QTC INTERVAL CHANGE FROM BASELINE BY CATEGORY 
SAFETY POPULATION 
 
 
TIMEPOINT 
 
CATEGORY 
RETIGABINE 
 (N=XXX) 
 
 
 
MONTH 1 
CHANGE FROM BASELINE IN QTc INTERVAL 
(MS) 
 
 
FRIDERICIA’S CORRECTION 
 
 
   <= 30 
xx (xx.x%) 
 
(30, 60] 
xx (xx.x%) 
 
    > 60 
xx (xx.x%) 
 
 
 
 
BAZETT’S CORRECTION 
 
 
   <= 30 
xx (xx.x%) 
 
(30, 60] 
xx (xx.x%) 
 
    > 60 
xx (xx.x%) 
 
 
 
 
 
REPEAT FOR TIMEPOINTS MONTH 3, MONTH 6, MONTH 9, MONTH 12, MONTH 24, MONTH 36 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 65 of 148 
 
 
 
 
TABLE 30  OBSERVED MEANS AND STANDARD DEVIATIONS OF QTC INTERVALS AND CHANGE FROM BASELINE BY MONTH 
SAFETY POPULATION 
 
RETIGABINE 
(N=XXX) 
 
 
 
 
TIMEPOINT 
 
 
 
n 
 
 
Mean (STD) 
Change from 
Baseline  
Mean (STD) 
 
 
 
 
ABSOLUTE QTc (FRIDERICIA’S) INTERVAL (MS) 
 
 
 
MONTH 1 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
MONTH 3 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
MONTH 6 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
MONTH 9 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
MONTH 12 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
MONTH 24 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
MONTH 36 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
 
ABSOLUTE QTc (BAZETT’S) INTERVAL (MS) 
 
 
 
MONTH 1 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
MONTH 3 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
MONTH 6 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
MONTH 9 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
MONTH 12 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
MONTH 24 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
MONTH 36 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 66 of 148 
 
 
 
 
TABLE 31  OBSERVED MEANS AND STANDARD DEVIATIONS OF VITAL SIGN RESULTS AND CHANGE FROM BASELINE BY MONTH 
SAFETY POPULATION 
 
RETIGABINE 
(N=XXX) 
 
 
 
 
PARAMETER (PARAMETER UNIT) 
 
 
 
 
TIMEPOINT 
 
 
n 
 
 
Mean (STD) 
Change from 
Baseline  
Mean (STD) 
 
 
 
 
 
SUPINE SBP (MMHG) 
BASELINE 
xxx 
xx.x (xx.xx) 
 
 
MONTH 1 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 3 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 6 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 9 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 12 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 16 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 20 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 24 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 28 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 32 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 36 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
 
 
SUPINE DBP (MMHG) 
: 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 67 of 148 
 
 
 
TABLE 32  NUMBER (%) OF PATIENTS WITH ORTHOSTATIC HYPOTENSION 
SAFETY POPULATION 
 
 
TIMEPOINT 
 
RETIGABINE 
 (N=XXX) 
 
 
 
BASELINE 
N 
xx 
 
YES 
xx (xx.x%) 
 
NO 
xx (xx.x%) 
 
 
 
MONTH 1 
N 
xx 
 
YES 
xx (xx.x%) 
 
NO 
xx (xx.x%) 
 
 
 
MONTH 3 
N 
xx 
 
YES 
xx (xx.x%) 
 
NO 
xx (xx.x%) 
 
 
 
MONTH 6 
N 
xx 
 
YES 
xx (xx.x%) 
 
NO 
xx (xx.x%) 
 
 
 
MONTH 9 
N 
xx 
 
YES 
xx (xx.x%) 
 
NO 
xx (xx.x%) 
 
 
 
MONTH 12 
N 
xx 
 
YES 
xx (xx.x%) 
 
NO 
xx (xx.x%) 
 
 
 
 
 
REPEAT FOR TIMEPOINTS MONTH 16, MONTH 20, MONTH 24, MONTH 28, MONTH 32 AND MONTH 36 
 
 
 
 
 
 
 
FOOTNOTES: 
ORTHOSTATIC HYPOTENSION IS DEFINED AS EITHER A DECREASE IN SBP>=20 MMHG UPON STANDING OR DECREASE IN DBP>=10 MMHG UPON STANDING 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 68 of 148 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
VRX-RET-E22-304 
69


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 69 of 148 
 
 
TABLE 33  NUMBER (%) OF PATIENTS WITH ABNORMAL RESULTS OF PHYSICAL EXAMINATIONS 
SAFETY POPULATION 
 
 
TIMEPOINT 
PHYSICAL 
EXAMINATION 
 
 
RETIGABINE 
 (N=XXX) 
 
 
 
 
BASELINE 
SKIN 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
HEAD 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
EYES 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
EARS 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
NOSE 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
THROAT 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
MOUTH 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
NECK 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
CHEST 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
HEART 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
REPEAT FOR TIMEPOINTS MONTH 12, MONTH 24 AND MONTH 36 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 70 of 148 
 
 
 
TABLE 33  NUMBER (%) OF PATIENTS WITH ABNORMAL RESULTS OF PHYSICAL EXAMINATIONS 
SAFETY POPULATION 
 
 
TIMEPOINT 
PHYSICAL 
EXAMINATION 
 
 
RETIGABINE 
 (N=XXX) 
 
 
 
 
BASELINE 
LUNGS 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
BREAST 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
ABDOMEN 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
GENITALIA 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
EXTREMITIES 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
OTHER 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
 
REPEAT FOR TIMEPOINTS MONTH 12, MONTH 24 AND MONTH 36 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 71 of 148 
 
 
TABLE 34  NUMBER (%) OF PATIENTS WITH ABNORMAL RESULTS OF NEUROLOGICAL EXAMINATIONS 
SAFETY POPULATION 
 
 
TIMEPOINT 
 
 
 
RETIGABINE 
 (N=XXX) 
 
 
 
 
BASELINE  
NEUROLOGICAL EXAMINATION – COMPLETE 
 
 
 
GENERAL 
 
 
 
LEVEL OF CONSCIOUSNESS 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
LEVEL OF APPEARANCE/MOTOR EXPRESSION 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
MENTAL STATUS 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
SPEECH 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
CRANIAL NERVES 
 
 
 
VISION 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
EYE MOVEMENTS 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
JAW MOVEMENT AND FACIAL SENSATION 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
FACIAL MOTOR 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
SWALLOWING, PHARYNX, LARYNX 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
STERNOCLEIDOMASTOID, TRAPEZIUS 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
TONGUE 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 72 of 148 
 
 
 
TABLE 34  NUMBER (%) OF PATIENTS WITH ABNORMAL RESULTS OF NEUROLOGICAL EXAMINATIONS 
SAFETY POPULATION 
 
 
TIMEPOINT 
 
 
RETIGABINE 
 (N=XXX) 
 
 
 
 
BASELINE 
NEUROLOGICAL EXAMINATION - COMPLETE 
 
 
 
REFLEXES 
 
 
 
BICEPS 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
BRACHIORADIALIS 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
TRICEPS 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
KNEE 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
ANKLE 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
PLANTAR 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
STERNOCLEIDOMASTOID, TRAPEZIUS 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
MOTOR SYSTEM 
 
 
 
GENERAL MOVEMENT 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
MUSCLE BULK/MASS 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
MUSCLE FASCICULATION 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
VRX-RET-E22-304 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 73 of 148 
 
 
TABLE 34  NUMBER (%) OF PATIENTS WITH ABNORMAL RESULTS OF NEUROLOGICAL EXAMINATIONS 
SAFETY POPULATION 
 
 
TIMEPOINT 
 
 
RETIGABINE 
 (N=XXX) 
 
 
 
 
BASELINE 
NEUROLOGICAL EXAMINATION - COMPLETE 
 
 
 
MUSCLE STRENGTH 
 
 
 
TRUNK   
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
UPPER EXTREMITIES 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
LOWER EXTREMITIES   
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
MUSCLE TONE 
 
 
 
UPPER EXTREMITIES 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
LOWER EXTREMITIES 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
COORDINATION/CEREBELLAR FUNCTION 
 
 
 
GAIT  
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
HOPPING                        
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
ROMBERG                        
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
NYSTAGMUS                      
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
TREMOR                         
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
VRX-RET-E22-304 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 74 of 148 
 
 
 
 
TABLE 34  NUMBER (%) OF PATIENTS WITH ABNORMAL RESULTS OF NEUROLOGICAL EXAMINATIONS 
SAFETY POPULATION 
 
 
TIMEPOINT 
 
 
RETIGABINE 
 (N=XXX) 
 
 
 
 
BASELINE 
NEUROLOGICAL EXAMINATION - COMPLETE 
 
 
 
COORDINATION/CEREBELLAR FUNCTION 
 
 
 
FINGER-NOSE 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
HEEL-SHIN 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
RAPID RHYTHMIC MOVEMENTS 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
SENSATION: UPPER EXTREMITIES 
 
 
 
PAIN/TEMPERATURE   
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
LIGHT TOUCH 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
POSITION 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
VIBRATION                
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
SENSATION: LOWER EXTREMITIES 
 
 
 
PAIN/TEMPERATURE   
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
LIGHT TOUCH 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 75 of 148 
 
 
 
 
TABLE 34  NUMBER (%) OF PATIENTS WITH ABNORMAL RESULTS OF NEUROLOGICAL EXAMINATIONS 
SAFETY POPULATION 
 
 
TIMEPOINT 
 
 
RETIGABINE 
 (N=XXX) 
 
 
 
 
BASELINE 
NEUROLOGICAL EXAMINATION - COMPLETE 
 
 
 
SENSATION: LOWER EXTREMITIES 
 
 
 
POSITION 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
VIBRATION                
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
MONTH 1 
NEUROLOGICAL EXAMINATION - BRIEF 
 
 
 
GENERAL 
 
 
 
LEVEL OF CONSCIOUSNESS 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
MENTAL STATUS 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
REFLEXES 
 
 
 
BICEPS 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
KNEE 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
MOTOR SYSTEM 
 
 
 
GENERAL MOVEMENT 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
VRX-RET-E22-304 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 76 of 148 
 
 
 
 
TABLE 34  NUMBER (%) OF PATIENTS WITH ABNORMAL RESULTS OF NEUROLOGICAL EXAMINATIONS 
SAFETY POPULATION 
 
 
TIMEPOINT 
 
 
RETIGABINE 
 (N=XXX) 
 
 
 
 
MONTH 1 
NEUROLOGICAL EXAMINATION - BRIEF 
 
 
 
COORDINATION/CEREBELLAR FUNCTION 
 
 
 
GAIT  
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
HOPPING                        
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
ROMBERG                        
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
NYSTAGMUS                      
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
TREMOR                         
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
FINGER-NOSE 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
HEEL-SHIN 
NORMAL 
xx (xx.x%) 
 
 
ABNORMAL 
xx (xx.x%) 
 
 
 
 
 
RAPID RHYTHMIC MOVEMENTS 
NORMAL 
xx (xx.x%) 
 
 
 
 
 
 
REPEAT IN ORDER OF VISITS USING THE PROPER FORMAT OF COMPLETE OR BRIEF DEPENDING UPON VISIT IE. BASELINE (COMPLETE), MONTH 1 (BRIEF), 
MONTH 3 (BRIEF), MONTH 6 (BRIEF), MONTH 9 (BRIEF), MONTH 12 (COMPLETE), MONTH 16 (BRIEF), MONTH 20 (BRIEF), MONTH 24 (COMPLETE), MOTH 
28 (BRIEF), MONTH 32 (BRIEF), MONTH 36 (COMPLETE) 
CONFIDENTIAL
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VRX-RET-E22-304 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 77 of 148 
 
 
 
 
TABLE 35  NUMBER (%) OF PATIENTS WITH ABNORMAL AUA SYMPTOM INDEX 
SAFETY POPULATION 
 
 
TIMEPOINT 
 
RETIGABINE 
 (N=XXX) 
 
 
 
BASELINE 
1. HOW OFTEN HAVE YOU HAD A SENSATION OF NOT EMPTYING YOUR BLADDER COMPLETELY? 
 
 
NOT AT ALL 
xx (xx.x%) 
 
LESS THAN 1 TIME IN 5 
xx (xx.x%) 
 
LESS THAN HALF TIME 
xx (xx.x%) 
 
ABOUT HALF THE TIME 
xx (xx.x%) 
 
MORE THAN HALF THE TIME 
xx (xx.x%) 
 
ALMOST ALWAYS 
xx (xx.x%) 
 
 
 
 
2. HOW OFTEN HAVE YOU HAS TO URINATE AGAIN LESS THAN 2 HOURS AFTER YOU FINISHED URINATING? 
 
 
NOT AT ALL 
xx (xx.x%) 
 
LESS THAN 1 TIME IN 5 
xx (xx.x%) 
 
LESS THAN HALF TIME 
xx (xx.x%) 
 
ABOUT HALF THE TIME 
xx (xx.x%) 
 
MORE THAN HALF THE TIME 
xx (xx.x%) 
 
ALMOST ALWAYS 
xx (xx.x%) 
 
 
 
 
3. HOW OFTEN HAVE YOU FOUND YOU STOPPED AND STARTED AGAIN SEVERAL TIMES WHEN YOU URINATED? 
 
 
NOT AT ALL 
xx (xx.x%) 
 
LESS THAN 1 TIME IN 5 
xx (xx.x%) 
 
LESS THAN HALF TIME 
xx (xx.x%) 
 
ABOUT HALF THE TIME 
xx (xx.x%) 
 
MORE THAN HALF THE TIME 
xx (xx.x%) 
 
ALMOST ALWAYS 
xx (xx.x%) 
 
 
 
 
4. HOW OFTEN HAVE YOU FOUND IT DIFFICULT TO POSTPONE URINATION? 
 
 
NOT AT ALL 
xx (xx.x%) 
 
LESS THAN 1 TIME IN 5 
xx (xx.x%) 
 
LESS THAN HALF TIME 
xx (xx.x%) 
 
ABOUT HALF THE TIME 
xx (xx.x%) 
 
MORE THAN HALF THE TIME 
xx (xx.x%) 
 
ALMOST ALWAYS 
xx (xx.x%) 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
VRX-RET-E22-304 
78


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 78 of 148 
 
 
 
TABLE 35  NUMBER (%) OF PATIENTS WITH ABNORMAL AUA SYMPTOM INDEX 
SAFETY POPULATION 
 
 
TIMEPOINT 
 
RETIGABINE 
 (N=XXX) 
 
 
 
BASELINE 
5. HOW OFTEN HAVE YOU HAD A WEAK URINARY STREAM? 
 
 
NOT AT ALL 
xx (xx.x%) 
 
LESS THAN 1 TIME IN 5 
xx (xx.x%) 
 
LESS THAN HALF TIME 
xx (xx.x%) 
 
ABOUT HALF THE TIME 
xx (xx.x%) 
 
MORE THAN HALF THE TIME 
xx (xx.x%) 
 
ALMOST ALWAYS 
xx (xx.x%) 
 
 
 
 
6. HOW OFTEN HAVE YOU HAD TO PUSH OR STRAIN TO BEGIN URINATION? 
 
 
NOT AT ALL 
xx (xx.x%) 
 
LESS THAN 1 TIME IN 5 
xx (xx.x%) 
 
LESS THAN HALF TIME 
xx (xx.x%) 
 
ABOUT HALF THE TIME 
xx (xx.x%) 
 
MORE THAN HALF THE TIME 
xx (xx.x%) 
 
ALMOST ALWAYS 
xx (xx.x%) 
 
 
 
 
7. HOW MANY TIMES DID YOU MOST TYPICALLY GET UP TO URINATE FROM THE TIME YOU WENT TO BED UNTIL 
THE TIME YOU GOT UP? 
 
 
NONE 
xx (xx.x%) 
 
1 TIME   
xx (xx.x%) 
 
2 TIMES 
xx (xx.x%) 
 
3 TIMES 
xx (xx.x%) 
 
4 TIMES 
xx (xx.x%) 
 
5 TIMES OR MORE 
xx (xx.x%) 
 
 
 
    
 
REPEAT FOR TIMEPOINTS MONTH 1, MONTH 3 AND MONTH 12 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 79 of 148 
 
 
 
TABLE 36 DESCRIPTIVE STATISTICS OF RAW OVERALL AUA SCORES 
SAFETY POPULATION 
 
 
RETIGABINE 
(N=XXX) 
 
 
 
TIMEPOINT 
 
 
 
STATISTICS 
OBSERVED 
CHANGE FROM 
BASELINE 
 
 
 
 
BASELINE 
N 
xxx 
 
 
MEAN 
xxx.x 
 
 
STD 
xxx.xx 
 
 
MEDIAN 
xxx.x 
 
 
MINIMUM 
xxx 
 
 
MAXIMUM 
xxx 
 
 
 
 
 
MONTH 1 
N 
xxx 
xxx 
 
MEAN 
xxx.x 
xxx.x 
 
STD 
xxx.xx 
xxx.xx 
 
MEDIAN 
xxx.x 
xxx.x 
 
MINIMUM 
xxx 
xxx 
 
MAXIMUM 
xxx 
xxx 
 
 
 
 
MONTH 3 
N 
xxx 
xxx 
 
MEAN 
xxx.x 
xxx.x 
 
STD 
xxx.xx 
xxx.xx 
 
MEDIAN 
xxx.x 
xxx.x 
 
MINIMUM 
xxx 
xxx 
 
MAXIMUM 
xxx 
xxx 
 
 
 
 
MONTH 12 
N 
xxx 
xxx 
 
MEAN 
xxx.x 
xxx.x 
 
STD 
xxx.xx 
xxx.xx 
 
MEDIAN 
xxx.x 
xxx.x 
 
MINIMUM 
xxx 
xxx 
 
MAXIMUM 
xxx 
xxx 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 80 of 148 
 
 
 
TABLE 37  NUMBER (%) OF PATIENTS WHO HAD MILD, MODERATE, SEVERE AUA SCORES  
SAFETY POPULATION 
 
 
 
TIMEPOINT 
 
CATEGORY 
RETIGABINE 
 (N=XXX) 
 
 
 
BASELINE 
N 
xx 
 
MILD [0,7] 
xx (xx.x%) 
 
MODERATE [8,19] 
xx (xx.x%) 
 
SEVERE (>19) 
xx (xx.x%) 
 
 
 
MONTH 1 
N 
xx 
 
MILD [0,7] 
xx (xx.x%) 
 
MODERATE [8,19] 
xx (xx.x%) 
 
SEVERE (>19) 
xx (xx.x%) 
 
 
 
MONTH 3 
N 
xx 
 
MILD [0,7] 
xx (xx.x%) 
 
MODERATE [8,19] 
xx (xx.x%) 
 
SEVERE (>19) 
xx (xx.x%) 
 
 
 
MONTH 3 
N 
xx 
 
MILD [0,7] 
xx (xx.x%) 
 
MODERATE [8,19] 
xx (xx.x%) 
 
SEVERE (>19) 
xx (xx.x%) 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 81 of 148 
 
 
TABLE 38  AUA CATEGORY SHIFT FROM BASELINE  
SAFETY POPULATION 
 
 
RETIGABINE 
(N=XXX) 
 
 
FROM BASELINE 
MILD [0,7] 
MODERATE[8,19] 
SEVERE (>19) 
 
 
 
 
TO MONTH 1 
 
 
 
MILD [0,7] 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
MODERATE [8,19] 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
SEVERE (>19) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
TO MONTH 3 
 
 
 
MILD [0,7] 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
MODERATE [8,19] 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
SEVERE (>19) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
TO MONTH 12 
 
 
 
MILD [0,7] 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
MODERATE [8,19] 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
SEVERE (>19) 
xx (xx.x%) 
xx (xx.x%) 
xx (xx.x%) 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 82 of 148 
 
 
 TABLE 39  NUMBER (%) OF PATIENTS WITH ABNORMAL PVR BLADDER ULTRASOUND  
SAFETY POPULATION 
 
 
TIMEPOINT 
 
CATEGORY 
RETIGABINE 
 (N=XXX) 
 
 
 
BASELINE 
N 
xx 
 
ABNORMAL 
xx (xx.x%) 
 
NORMAL 
xx (xx.x%) 
 
 
 
MONTH 1 
N 
xx 
 
ABNORMAL 
xx (xx.x%) 
 
NORMAL 
xx (xx.x%) 
 
 
 
MONTH 3 
N 
xx 
 
ABNORMAL 
xx (xx.x%) 
 
NORMAL 
xx (xx.x%) 
 
 
 
MONTH 12 
N 
xx 
 
ABNORMAL 
xx (xx.x%) 
 
NORMAL 
xx (xx.x%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 83 of 148 
 
 
 
TABLE 40  DESCRIPTIVE STATISTICS OF PVR BLADDER ULTRASOUND 
SAFETY POPULATION 
 
RETIGABINE 
 (N=XXX) 
 
 
TIMEPOINT 
 
 
STATISTIC 
ACTUAL 
CHANGE FROM BASELINE 
 
 
 
 
BASELINE 
N 
xxx 
 
 
MEAN 
xxx.x 
 
 
STD 
xxx.xx 
 
 
MEDIAN 
xxx.x 
 
 
MINIMUM 
xxx 
 
 
MAXIMUM 
xxx 
 
 
 
 
 
MONTH 1 
N 
xxx 
xxx 
  
MEAN 
xxx.x 
xxx.x 
 
STD 
xxx.xx 
xxx.xx 
 
MEDIAN 
xxx.x 
xxx.x 
 
MINIMUM 
xxx 
xxx 
 
MAXIMUM 
xxx 
xxx 
 
 
 
 
MONTH 3 
N 
xxx 
xxx 
  
MEAN 
xxx.x 
xxx.x 
 
STD 
xxx.xx 
xxx.xx 
 
MEDIAN 
xxx.x 
xxx.x 
 
MINIMUM 
xxx 
xxx 
 
MAXIMUM 
xxx 
xxx 
 
 
 
 
MONTH 12 
N 
xxx 
xxx 
  
MEAN 
xxx.x 
xxx.x 
 
STD 
xxx.xx 
xxx.xx 
 
MEDIAN 
xxx.x 
xxx.x 
 
MINIMUM 
xxx 
xxx 
 
MAXIMUM 
xxx 
xxx 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 84 of 148 
 
 
TABLE 41 NUMBER (%) OF PATIENTS WITH A CLINICALLY SIGNIFICANT PVR BLADDER ULTRASOUND  
SAFETY POPULATION 
 
 
TIMEPOINT 
 
CATEGORY 
RETIGABINE 
 (N=XXX) 
 
 
 
BASELINE 
N 
xx 
 
>50mL 
xx (xx.x%) 
 
>100mL 
xx (xx.x%) 
 
>150mL 
xx (xx.x%) 
 
 
 
MONTH 1 
N 
xx 
 
>50mL 
xx (xx.x%) 
 
>100mL 
xx (xx.x%) 
 
>150mL 
xx (xx.x%) 
 
 
 
MONTH 3 
N 
xx 
 
>50mL 
xx (xx.x%) 
 
>100mL 
xx (xx.x%) 
 
>150mL 
xx (xx.x%) 
 
 
 
MONTH 12 
N 
xx 
 
>50mL 
xx (xx.x%) 
 
>100mL 
xx (xx.x%) 
 
>150mL 
xx (xx.x%) 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
VRX-RET-E22-304 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 85 of 148 
 
 
TABLE 42  NUMBER (%) OF PATIENTS TAKING CONCOMITANT MEDICATIONS 
SAFETY POPULATION 
 
 
MEDICATION PREFERRED TERM 
RETIGABINE 
 (N=XXX) 
 
 
CONCOMITANT MEDICATION PREFERRED TERM 
xx (xx.x%) 
CONCOMITANT MEDICATION PREFERRED TERM 
xx (xx.x%) 
CONCOMITANT MEDICATION PREFERRED TERM 
xx (xx.x%) 
CONCOMITANT MEDICATION PREFERRED TERM 
xx (xx.x%) 
CONCOMITANT MEDICATION PREFERRED TERM 
xx (xx.x%) 
CONCOMITANT MEDICATION PREFERRED TERM 
xx (xx.x%) 
CONCOMITANT MEDICATION PREFERRED TERM 
xx (xx.x%) 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 86 of 148 
 
 
TABLE 43  OBSERVED MEANS AND STANDARD DEVIATIONS OF QOL IN EPILEPSY (QOLIE-31-P) AND CHANGE FROM BASELINE BY MONTH  
SAFETY POPULATION 
 
 
RETIGABINE 
 (N=XXX) 
 
 
 
 
CATEGORY 
 
 
 
 
TIMEPOINT 
 
 
n 
 
 
Mean (STD) 
Change from 
Baseline  
Mean (STD) 
 
 
 
 
 
OVERALL ASSESSMENT 
BASELINE 
xxx 
xx.x (xx.xx) 
 
 
MONTH 3 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 6 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 9 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 12 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 24 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 36 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
 
 
EMOTIONAL/PYSCHOLOGICAL EFFECTS DOMAIN 
BASELINE 
xxx 
xx.x (xx.xx) 
 
 
MONTH 3 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 6 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 9 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 12 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 24 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 36 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
 
 
MEDICAL/SOCIAL EFFECTS DOMAIN 
BASELINE 
xxx 
xx.x (xx.xx) 
 
 
MONTH 3 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 6 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 9 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 12 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 24 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
MONTH 36 
xxx 
xx.x (xx.xx) 
xx.x (xx.xx) 
 
 
 
 
 
  
 
  
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
  
 
 
Filename: 87272_304_SAP_v2_final 
 
page 87 of 148 
 
 
11 FIGURE SHELLS 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
  
 
 
Filename: 87272_304_SAP_v2_final 
 
page 88 of 148 
 
 
FIGURE 1  MEDIAN PERCENT REDUCTION FROM BASELINE IN SEIZURE FREQUENCY OVER TIME BY DURATION OF TREATMENT EXPOSURE 
SAFETY POPULATION 
 
0
10
20
30
40
50
60
70
80
90
100
0
1
3
6
9
12
16
20
24
28
32
36
Months
Median % reduction from baseline
1m (N=xxx)
3m (N=xxx)
6m (N=xxx)
9m (N=xxx)
12m (N=xxx)
16m (N=xxx)
20m (N=xxx)
24m (N=xxx)
28m (N=xxx)
32m (N=xxx)
36m (N=xxx)
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
  
 
 
Filename: 87272_304_SAP_v2_final 
 
page 89 of 148 
 
 
12 PATIENT DATA LISTING SHELLS 
 
CONFIDENTIAL
RM2009/00475/00 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 90 of 148 
 
 
 
 
LISTING 1  PATIENT WITHDRAWAL/STUDY COMPLETION 
 
 
SITE 
PATIENT 
ID 
INITIALS 
AGE 
GENDER 
RACE 
STATUS 
DATE OF 
TAPERING DOSE 
IF 
DISCONTINUED 
IF DISCONTINUED, 
STUDY DRUG DISPENSED 
OR USED? 
PRIMARY REASON OF 
DISCONTINUATION 
SECONDARY 
REASON(S) OF 
DISCONTINUATION 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
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91
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 91 of 148 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
VRX-RET-E22-304 
92


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 92 of 148 
 
 
LISTING 2  INCLUSION/EXCLUSION CRITERIA/ELIGIBILITY 
 
 
--- INCLUSION CRITERIA --- 
--EXCLUSION CRITERIA-- 
ELIGIBLE 
PATIENT ID 
AGE/GENDER/RACE 
Q1 
Q2 
Q3 
Q4 
05 
Q1 
Q2 
Q3 
Q1 
Q2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
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93
This section contained data from each individual patient, rather than in aggregate. They have 
been excluded to protect patient privacy. Anonymized data from each patient may be made 
available subject to an approved research proposal. For further information please see the 
Patient Level Data section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 93 of 148 
 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
VRX-RET-E22-304 
94


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 94 of 148 
 
 
  
LISTING 3  DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PATIENT 
ID 
AGE/GENDER/RACE 
CONSENT 
DATE 
(STUDY DAY) 
BASELINE 
DATE  
(DAY 0) 
START DATE 
OF EXTENSION 
STUDY MED. 
(STUDY DAY) 
HEIGHT
(cm)/ 
WEIGHT 
(kg) 
BMI 
(kg/m²) 
CLINICAL 
GLOBAL 
IMPRESSIONS 
SEVERITY 
DURATION 
OF 
ILLNESS 
(YEARS) 
TREATMENT/
STUDY 
DURATION 
(DAYS) 
 
NUMBER OF 
BACKGROUND 
AEDS 
COMPLETED 
STUDY? 
CONFIDENTIAL
RM2009/00475/00 
VRX-RET-E22-304 
95
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 95 of 148 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
VRX-RET-E22-304 
96


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 96 of 148 
 
 
 
LISTING 4  STUDY MEDICATION COMPLIANCE  
 
 
50 MG 
100 MG 
300 MG 
PATIENT 
ID 
AGE/GENDER/RACE 
STUDY VISIT 
DATE 
OF 
FIRST 
DOSE 
DATE 
OF 
LAST 
DOSE 
PRESCRIBED 
DOSE  
(MG/DAY) 
NUMBER OF 
TABLETS 
DISPENSED 
NUMBER 
OF 
TABLETS 
RETURNED 
NUMBER OF  
TABLETS  
DISPENSED 
NUMBER 
OF 
TABLETS 
RETURNED 
NUMBER OF 
TABLETS  
DISPENSED 
NUMBER 
OF 
TABLETS 
RETURNED 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
VRX-RET-E22-304 
97
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. 
Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see 
the Patient Level Data section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 97 of 148 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
VRX-RET-E22-304 
98


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 98 of 148 
 
 
 
LISTING 5  CONCOMITANT MEDICATIONS EXCLUDING BACKGROUND ANTI-EPILEPTIC DRUGS (AEDs) 
 
 
PATIENT ID 
AGE/GENDER/RACE 
REPORTED TERM 
PREFERRED TERM 
PRIMARY ATC CLASSIFICATION 
TOTAL DAILY DOSE 
AND UNITS 
START DATE 
STOP DATE 
ONGOING? 
NOTE THIS IS FROM DERIVED CM DATA SET WHERE CMTYPE = 2 AND THE CMREAS is not B or F 
NOTE THAT THERE APPEARS TO BE SOME ANTI-EPILEPTIC DRUGS THAT HAVE A CMREAS OTHER THAN B OR F IN THIS LISTING THIS IS BEING MEDICALLY REVIEWED. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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99
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 99 of 148 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
VRX-RET-E22-304 
100


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 100 of 148 
 
 
 
LISTING 6  CONCOMITANT TREATMENTS OTHER THAN MEDICATION 
 
 
PATIENT ID 
AGE/GENDER/RACE 
REPORTED TERM 
REASON FOR TREATMENT 
SPECIFY 
START DATE 
STOP DATE 
ONGOING? 
NOTE THIS IS FROM DERIVED CT DATA SET WHERE CTTERM IS NOT MISSING 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
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101
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 101 of 148 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 102 of 148 
 
 
LISTING 7  PARTIAL SEIZURE FREQUENCY 
 
 
 
 
 
 
 
----SIMPLE PARTIAL SEIZURES---- 
 
 
 
PATIENT 
ID 
AGE/GENDER/RACE 
VISIT 
DID SEIZURES 
OCCUR SINCE 
LAST VISIT 
DATE OF SEIZURE 
(STUDY DAY) 
WITH 
MOTOR 
SIGNS  
WITHOUT MOTOR 
SIGNS 
COMPLEX 
PARTIAL 
SEIZURES 
FLURRIES 
PARTIAL 
EVOLVING TO 
SECONDARILY 
GENERALIZED 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 103 of 148 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 104 of 148 
 
 
 
 
LISTING 8  GENERALIZED OR UNCLASSIFIED SEIZURE FREQUENCY 
 
 
PATIENT 
ID 
AGE/GENDER/RACE 
VISIT 
DID SEIZURES 
OCCUR SINCE 
LAST VISIT 
DATE OF 
SEIZURE 
(STUDY 
DAY) 
ABSENCE 
SEIZURES 
MYOCLONIC 
SEIZURES 
TONIC-
CLONIC 
SEIZURES 
ATONIC 
PARITAL 
STATUS 
EPILEPTICUS 
CONVULSIVE 
STATUS 
EPILEPTICUS 
UNCLASSIFIED 
SEIZURES 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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105
This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 105 of 148 
 
 
 
 
 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 106 of 148 
 
 
 
LISTING 9  EXTENT OF EXPOSURE TO STUDY MEDICATION 
 
 
PATIENT 
ID 
AGE/GENDER/RACE 
 
 
STUDY VISIT 
 
TREATMENT START 
DATE 
 
TREATMENT 
STOP DATE 
 
 
TOTAL DOSE (MG) 
AVERAGE DAILY 
DOSE OF STUDY 
MEDICATION 
(MG/DAY) 
EXTENT OF 
EXPOSURE 
(DAYS) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient 
privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further 
information please see the Patient Level Data section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 107 of 148 
 
 
  
LISTING 10  ADVERSE EVENTS CODING DICTIONARY MAPPING 
 
 
SYSTEM ORGAN CLASS 
PREFERRED TERM 
REPORTED TERM 
 
 
 
SOC 1 
PREFERRED TERM 1 
REPORTED TERM 1 
 
 
REPORTED TERM 2 
 
PREFERRED TERM 2 
REPORTED TERM 1 
 
: 
 
 
 
 
SOC 2 
PREFERRED TERM 1 
REPORTED TERM 1 
 
 
REPORTED TERM 2 
 
PREFERRED TERM 2 
REPORTED TERM 1 
: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 108 of 148 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 109 of 148 
 
 
LISTING 11  ADVERSE EVENTS  
 
 
SITE 
PATIENT 
ID 
AGE/GENDER/RACE 
REPORTED 
TERM 
PREFERRED 
TERM 
START 
DATE 
(STUDY 
DAY) 
STOP DATE 
INTENSITY 
RELATIONSHIP 
 
 
ACTION(S) 
TAKEN 
OUTCOME 
SAE? 
 
 
THE FORMAT ABOVE SHOULD BE REPEATED FOR THE FOLLOWING LISTINGS: 
LISTING 12  TREATMENT-EMERGENT ADVERSE EVENTS 
LISTING 13  TREATMENT-EMERGENT ADVERSE EVENTS AT LEAST POSSIBLY RELATED TO STUDY MEDICATION 
LISTING 14  TREATMENT-EMERGENT ADVERSE EVENTS THAT CAUSED WITHDRAWAL FROM STUDY 
LISTING 15  TREATMENT-EMERGENT ADVERSE EVENTS THAT LEAD TO DOSE MODIFICATION/INTERRUPTION 
 
LISTING 16  DEATHS  
NOTE THAT THIS IS WHERE AEOUT = 4 FATAL IF NO DEATHS THEN ‘NONE REPORTED’ SHOULD BE DISPLAYED 
 
LISTING 17  SERIOUS TREATMENT-EMERGENT ADVERSE EVENTS 
IF NO SERIOUS TREATMENT-EMERGENT ADVERSE EVENTS THEN ‘NONE REPORTED’ SHOULD BE DISPLAYED 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. 
Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see 
the Patient Level Data section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 110 of 148 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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VRX-RET-E22-304 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 111 of 148 
 
 
 
 
LISTING 18  LABORATORY REFERENCE RANGES 
 
 
LABORATORY 
PARAMETER 
 SI LAB UNIT 
NORMAL RANGE 
LOWER LIMIT 
(SI) 
NORMAL RANGE 
UPPER LIMIT 
(SI) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 112 of 148 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 113 of 148 
 
 
 
LISTING 19  HEMATOLOGY LABORATORY TEST RESULTS 
 
PATIENT 
ID 
AGE/GENDER/RACE 
VISIT 
COLLECTION DATE 
(STUDY DAY) 
WBC 
X10E3/UL 
RBC 
X10E6/UL 
HGB 
g/dL 
HCT 
% 
PLATELET 
COUNT 
X10E3/UL 
LYMPH 
% 
LYMPH, ABS 
X10E3/UL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. 
Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the 
Patient Level Data section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 114 of 148 
 
 
 
 
FOOTNOTES:                                                                                                              
* INDICATES A REPEAT VISIT.                                                                                              
H = HIGH.                                                                                                                
L = LOW.   
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 115 of 148 
 
 
 
LISTING 19  HEMATOLOGY LABORATORY TEST RESULTS 
 
 
PATIENT 
ID 
AGE/GENDER/RACE 
VISIT 
COLLECTION DATE 
(STUDY DAY) 
MONO 
% 
MONO, 
ABS, 
X10E3/UL 
EOS 
% 
EOS,  
ABS 
X10E3/UL 
BASO 
% 
BASO, 
ABS 
X10E3/UL 
NEUT 
% 
NEUT, 
ABS 
X10E3/UL 
MORPHOLOGY 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 116 of 148 
 
 
 
 
FOOTNOTES: 
* INDICATES A REPEAT VISIT.                                                                                              
H = HIGH.                                                                                                                
L = LOW. 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 117 of 148 
 
 
 
LISTING 20  BLOOD SERUM CHEMISTRY LABORATORY TEST RESULTS 
 
 
PATIENT 
ID 
AGE/GENDER/RACE 
VISIT 
COLLECTION DATE 
(STUDY DAY) 
ALT 
SGPT 
IU/L 
AST 
SGOT 
IU/L 
ALK. 
PHOS. 
IU/L 
TOT. 
BILI. 
mg/dL 
CREA. 
mg/dL 
BUN 
md/dL 
CHOL. 
mg/dL 
PHOS. 
mg/dL 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. 
Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the 
Patient Level Data section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 118 of 148 
 
 
 
 
FOOTNOTES: 
* INDICATES A REPEAT VISIT.                                                                                              
H = HIGH.                                                                                                                
L = LOW. 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 119 of 148 
 
 
 
LISTING 20  BLOOD SERUM CHEMISTRY LABORATORY TEST RESULTS 
 
 
PATIENT 
ID 
AGE/GENDER/RACE 
VISIT 
COLLECTION DATE 
(STUDY DAY) 
GLUCOSE 
mg/dL 
TOT. 
PROT. 
g/dL 
URIC ACID 
mg/dL 
CA 
mg/dL 
NA 
mEq/L 
K 
mEq/L 
Cl 
mEq/L 
BICARBONATE 
mEq/L 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 120 of 148 
 
 
 
 
FOOTNOTES: 
* INDICATES A REPEAT VISIT.                                                                                              
H = HIGH.                                                                                                                
L = LOW. 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 121 of 148 
 
 
  
LISTING 21  URINALYSIS LABORATORY TEST RESULTS 
 
 
PATIENT 
ID 
AGE/GENDER/RACE 
VISIT 
COLLECTION DATE 
(STUDY DAY) 
pH 
SPEC. 
GRAV. 
 
PROTEIN 
KETONES 
GLUCOSE 
BLOOD 
WBC 
/HPF 
RBC 
/HPF 
LEUK. 
ESTER. 
BACTERIA 
EPI. 
CELLS 
 
Note:  This listing should also contain any urinalysis results for crystals. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data 
from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of 
the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 122 of 148 
 
 
 
 
FOOTNOTES: 
* INDICATES A REPEAT VISIT.                                                                                              
H = HIGH.                                                                                                                
L = LOW. 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 123 of 148 
 
 
 
LISTING 22 ECG DIAGNOSIS/COMMENTS INFORMATION 
 
 
PATIENT ID 
INITIALS 
AGE/GENDER/RACE 
VISIT 
ECG DATE (STUDY 
DAY) 
ECG 
TIME 
ECG 
QUALITY 
DIAGNOSIS 
OVERALL ECG 
INTERPRETATION 
ECG COMMENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data 
from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of 
the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 124 of 148 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
VRX-RET-E22-304 
125


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 125 of 148 
 
 
 
LISTING 23  ECG RESULTS 
 
 
PATIENT ID 
INITIALS 
AGE/GENDER/RACE 
VISIT 
ECG DATE 
ECG TIME 
HR 
RR 
PR 
QRS 
QT 
AXIS 
QTcB 
QTcF 
NOTE ONLY RECORDS WITH AT LEAST 1 NON-MISSING RESULT WILL BE PRESENTED IN THIS LISTING 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
VRX-RET-E22-304 
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 126 of 148 
 
 
 
 
 
FOOTNOTES: 
1 PATIENT HAD AN INTERVAL >500MSEC OR CHANGE FROM BASELINE IN QTC INTERVAL >60MSEC 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 127 of 148 
 
 
 
LISTING 24  ECGS NOT PERFORMED AND THEIR REASON FOR NOT PERFORMING 
 
 
 
 
PATIENT ID 
INITIALS 
AGE/GENDER/RACE 
VISIT 
REASON FOR NOT PERFORMING ECG 
NOTE ONLY RECORDS WHERE THE VALUE OF THE ECGRES VARIABLE IS NON-MISSING SHOULD BE LISTED HERE. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 128 of 148 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
RM2009/00475/00 
VRX-RET-E22-304 
129


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 129 of 148 
 
 
  
LISTING 25 ECG RESULTS FOR PATIENTS WITH QTC INTERVAL >500MSEC OR CHANGE FROM BASELINE IN QTC INTERVAL >60MSEC 
 
 
TREATMENT DOSE 
(MG/DAY) 
PATIENT ID 
INITIALS 
AGE/GENDER/RACE 
VISIT 
ECG DATE 
ECG 
TIME 
DAY 
BEFORE 
ECG  
DAY OF 
ECG 
HR 
RR 
PR 
QRS 
QT 
AXIS 
QTcB 
QTcF 
NOTE ONLY RECORDS WITH AT LEAST 1 NON-MISSING RESULT WILL BE PRESENTED IN THIS LISTING 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 130 of 148 
 
 
 
 
 
 
FOOTNOTES: 
1 PATIENT HAD AN INTERVAL >500MSEC OR CHANGE FROM BASELINE IN QTC INTERVAL >60MSEC 
CONFIDENTIAL
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VRX-RET-E22-304 
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 131 of 148 
 
 
 
LISTING 26  VITAL SIGNS 
 
 
PATIENT 
ID 
AGE/GENDER/RACE 
VISIT 
DATE OF VITAL 
SIGNS  
(STUDY DAY) 
SUPINE 
SYSTOLIC 
mmHg 
SUPINE 
DIASTOLIC 
mmHg 
SUPINE 
PULSE 
bpm 
STANDING 
SYSTOLIC 
mmHg 
STANDING 
DIASTOLIC 
mmHg 
STANDING 
PULSE 
bpm 
WEIGHT 
kg 
TEMP. 
°C 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 132 of 148 
 
 
 
 
 
 
 
FOOTNOTE: 
* INDICATES A >=7% INCREASE IN BODY WEIGHT FROM BASELINE 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 133 of 148 
 
 
 
LISTING 27  ABNORMAL PHYSICAL EXAMINATION RESULTS 
 
 
PATIENT 
ID 
AGE/GENDER/RACE 
VISIT 
DATE OF EXAM 
(STUDY DAY) 
BODY SYSTEM 
REPORTED ABNORMALITY 
NOTE UNDER BODY SYSTEM IS THE VALUES OF EITHER THE NON-MISSING PEBODSYS VARIABLE VALUE OR THE PEOTHER VARIABLE VALUE IF PEBODSYS IS MISSING. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 134 of 148 
 
 
 
 
 
CONFIDENTIAL
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VRX-RET-E22-304 
135


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 135 of 148 
 
 
LISTING 28 ABNORMAL NEUROLOGICAL EXAMINATION RESULTS 
 
 
PATIENT 
ID 
AGE/GENDER/RACE 
VISIT 
DATE OF EXAM 
(STUDY DAY) 
EXAM GROUP 
GROUP PARAMETER 
REPORTED ABNORMALITY 
CLINICALLY 
SIGNIFICANT? 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
CONFIDENTIAL
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 136 of 148 
 
 
 
 
 
 
 
CONFIDENTIAL
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Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 137 of 148 
 
 
LISTING 29  AUA SYMPTOM INDEX 
 
PATIENT ID 
AGE/GENDER/RACE 
VISIT 
DATE OF EXAM 
(STUDY DAY) 
Q1 
Q2 
Q3 
Q4 
Q5 
Q6 
Q7 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
FOOTNOTES: 
QUESTION 1 HOW OFTEN HAVE YOU HAD A SENSATION OF NOT EMPTYING YOUR BLADDER COMPLETELY AFTER YOU FINISHED URINATING? 
CONFIDENTIAL
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
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QUESTION 2 HOW OFTEN HAVE YOU HAD TO URINATE AGAIN LESS THAN 2 HOURS AFTER YOU FINISHED URINATING? 
QUESTION 3 HOW OFTEN HAVE YOU FOUND YOU STOPPED AND STARTED AGAIN SEVERAL TIMES WHEN YOU URINATED? 
QUESTION 4 HOW OFTEN HAVE YOU FOUND IT DIFFICULT TO POSTPONE URINATION? 
QUESTION 5 HOW OFTEN HAVE YOU HAD A WEAK URINARY STREAM? 
QUESTION 6 HOW OFTEN HAVE YOU HAD TO PUSH OR STRAIN TO BEGIN URINATION? 
QUESTION 7 HOW MANY TIMES DID YOU MOST TYPICALLY GET UP TO URINATE FROM THE TIME YOU WENT TO BED AT NIGHT UNTIL THE TIME YOU GOT UP? 
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Statistical Analysis Plan 
VRX-RET-E22-304 
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LISTING 30  PVR BLADDER ULTRASOUND RESULTS 
 
PATIENT ID 
AGE/GENDER/RACE 
VISIT 
DATE OF EXAM 
(STUDY DAY) 
INTERPRETATION 
PVR URINE VOLUME  
(mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
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Filename: 87272_304_SAP_v2_final 
 
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Statistical Analysis Plan 
VRX-RET-E22-304 
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Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
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LISTING 31  QUALITY OF LIFE IN EPILEPSY SCORES (QOLIE-31-P) 
 
 
 
 
 
 
 
--------PART A-------- 
------------PART B------------ 
--------------PARTC-------------- 
PATIENT 
ID 
AGE/GENDER/RACE 
VISIT 
DATE OF EXAM 
(STUDY DAY) 
Q1 
Q2 
Q3 
Q4 
Q5 
Q6 
Q7 
Q8 
Q9 
Q10 
Q11 
Q12 
Q13 
Q14 
Q15 
Q16 
Q17 
Q18 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
page 142 of 148 
 
 
 
 
 
 
 
 
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Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
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LISTING 31  QUALITY OF LIFE IN EPILEPSY SCORES (QOLIE-31-P) 
 
 
 
 
 
 
----------------PART D---------------- 
-------PART E------- 
--------------PART F------------- 
PATIENT 
ID 
AGE/GENDER/RACE 
VISIT 
DATE OF EXAM 
(STUDY DAY) 
Q19 
Q20 
Q21 
Q22 
Q23 
Q24 
Q25 
Q26 
Q27 
Q28 
Q29 
Q30 
Q31 
Q32 
Q33 
Q34 
Q35 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
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Run Date: 
 
 
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Statistical Analysis Plan 
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LISTING 31   QUALITY OF LIFE IN EPILEPSY SCORES (QOLIE-31-P) 
 
 
 
 
 
 
---PART G--- 
PART H 
--------------------------PART I-------------------------- 
PATIENT ID 
AGE/GENDER/RACE 
VISIT 
DATE OF EXAM 
(STUDY DAY) 
Q36 
Q37 
Q38 
Q39A 
Q39B 
Q39C 
Q39D 
Q39E 
Q39F 
Q39G 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized 
data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data 
section of the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
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Statistical Analysis Plan 
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LISTING 31  QUALITY OF LIFE IN EPILEPSY SCORES (QOLIE-31-P) 
 
 
 
 
 
----------------------------------------------SCORING---------------------------------------------- 
PATIENT 
ID 
AGE/GENDER/RACE 
VISIT 
DATE OF EXAM 
(STUDY DAY) 
SEIZURE 
WORRY 
SCORE 
OVERALL 
QOL SCORE 
EMOTIONAL 
WELL BEING 
ENERGY 
FATIGUE 
SCORE 
COGNITIVE 
SCORE 
MEDICATION 
EFFECTS SCORE 
SOCIAL 
FUNCTIONING 
SCORE 
OVERALL 
SCORE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data 
from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of 
the Sponsor Clinical Study Register. 


Valeant Pharmaceuticals North America 
Statistical Analysis Plan 
VRX-RET-E22-304 
Version 2.0 [Final] 
 
 
Valeant Pharmaceuticals North America              
 
 
 
 
 
 
 
 
 
PAGE X OF X 
Protocol Number: VRX-RET-E22-304  
 
Program Path/sas program name  
 
 
 
 
 
 
 
 
 
 
 
Run Date: 
 
 
Filename: 87272_304_SAP_v2_final 
 
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