Clinical trial NCT04912856
Conditions: Epilepsy Epilepsy in Children Epilepsy; Seizure Disease Brain Diseases Central Nervous System Diseases Nervous System Diseases Epileptic Syndromes
Keywords: XEN496 Ezogabine Retigabine Encephalopathy Seizure KCNQ2 EPIK
Sponsor: Xenon Pharmaceuticals Inc.
Start date: 2021-08-17; Completion date: 2023-11-17
Enrollment: 8 participants; Allocation: NON_RANDOMIZED; Intervention model: SEQUENTIAL

Brief summary:
To assess the long-term safety and tolerability of XEN496 in pediatric subjects with KCNQ2 developmental and epileptic encephalopathy (KCNQ2-DEE) who had participated in the primary study (XPF-009-301).

Detailed description:
This is an open-label, long-term extension study of XEN496 for the treatment of seizures in subjects with KCNQ2-DEE, that will be open to eligible subjects who participated in the primary study, XPF-009-301. The primary objective is to assess the long-term safety of XEN496. A double-blind transition/titration period will be used to maintain blinding to the treatment allocation in the primary study (XPF-009-301). After completion of the blinded transition/titration period, subjects will receive the open label study drug at their optimal dose for approximately 35 months.

Arms: arm 1: 24-day blinded transition/titration period. Subjects who received XEN496 in the preceding study will continue to receive XEN496 at the same dose, in a blinded manner, without any further titration. To maintain the blinded aspect of the study, placebo will be dispensed to all subjects during the transition/titration period to ensure the total number of capsules are consistent across all subjects.

Subjects who discontinue will be required to taper off study drug over a period of up to 15 days arm 2: 24-day blinded transition/titration period. Subjects who were allocated to placebo in the preceding study, will be titrated to a tolerated dose up to a maximum dose of 21 mg/kg/day, with a maximum daily dose of 672 mg/day. To maintain the blinded aspect of the study, placebo will be dispensed to all subjects during the transition/titration period to ensure the total number of capsules are consistent across all subjects

Subjects who discontinue or complete the study treatment will be required to taper off study drug over a period of up to 15 days.
Interventions: intervention 1: XEN496
Intervention descriptions: intervention 1: XEN496 sprinkle capsules. Parents / caregivers will be instructed to sprinkle and mix the contents of the capsules into soft foods or liquids and feed it to the child.

Protocol documents:
Prot_SAP_001.pdf: 
 
 
PROTOCOL 
 
AN OPEN-LABEL EXTENSION STUDY OF XEN496 IN PEDIATRIC SUBJECTS 
WITH KCNQ2 DEVELOPMENTAL AND EPILEPTIC ENCEPHALOPATHY 
 
 
 
Sponsor: 
Xenon Pharmaceuticals Inc. 
200-3650 Gilmore Way 
Burnaby, BC 
V5G 4W8 
Canada 
Study Number: 
XPF-009-302 
Clinical Study 
Identifier: 
EPIK OLE 
IND Number: 
138144 
EudraCT Number: 
2020-003447-28 
Compound: 
Ezogabine (USAN)/Retigabine (INN) 
Version: 
3.0 
Date: 
09 May 2022 
Previous Versions: 
• 2.0, dated 04 Apr 2022 
• 1.0, dated 29 Sept 2020 
 
 
 
CONFIDENTIALITY STATEMENT 
Information in this protocol is confidential and should not be disclosed, other than to those 
directly involved in the execution or the ethical/regulatory review of the study, without prior 
written authorization from Xenon Pharmaceuticals Inc. or its affiliates. 


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STATEMENT OF COMPLIANCE 
The study will be carried out in accordance with the protocol, International Council for 
Harmonisation of Technical Requirements for Pharmaceuticals for Human Use-Good Clinical 
Practice (ICH-GCP) and applicable regulatory requirements. 
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the ethics committee/institutional review board (EC/IRB) for review and approval. 
Approval of both the protocol and the consent form must be obtained before any subject is 
enrolled. Any amendment to the protocol will require review and approval by the EC/IRB. In 
addition, all changes to the consent form will be EC/IRB-approved; a determination will be made 
regarding whether a new consent needs to be obtained from subjects who provided consent, 
using a previously approved consent form. 
 


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SPONSOR APPROVAL 
STUDY TITLE: An Open-label Extension Study of XEN496 in Pediatric Subjects With 
KCNQ2 Developmental and Epileptic Encephalopathy 
 
I, the undersigned, have read this protocol and agree that it contains all necessary information 
required to conduct the study. 
 
SIGNATURES: 




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INVESTIGATOR AGREEMENT 
STUDY TITLE: An Open-label Extension Study of XEN496 in Pediatric Subjects With 
KCNQ2 Developmental and Epileptic Encephalopathy 
 
By signing below, I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design 
and specific provisions of this protocol and will make a reasonable effort to complete the study 
within the time designated. 
 
 
 
 
 understand that the study may be 
terminated or enrollment suspended at any time by Xenon, with or without cause, or by me if it 
becomes necessary to protect the best interests of the study subjects. 
I agree to conduct this study in full accordance with applicable local regulations, ethics 
committee/institutional review board regulations, and International Council for Harmonisation 
Guidelines for Good Clinical Practice. 
 
 
Investigator’s Signature 
Date 
 
 
Investigator’s Printed Name 
 


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COORDINATING INVESTIGATOR AGREEMENT 
STUDY TITLE: An Open-label Extension Study of XEN496 in Pediatric Subjects With 
KCNQ2 Developmental and Epileptic Encephalopathy 
 
By signing below, I agree that: 
I have read this protocol. I approve this document and I agree that it contains all necessary details 
for carrying out the study as described. I will conduct this study in accordance with the design 
and specific provisions of this protocol and will make a reasonable effort to complete the study 
within the time designated. 
 
 
 
 
 I understand that the study may be 
terminated or enrollment suspended at any time by Xenon, with or without cause, or by me if it 
becomes necessary to protect the best interests of the study subjects. 
I agree to the assigned responsibility for the coordination of investigators at different centers 
participating in the multicenter trial. 
I agree to conduct this study in full accordance with applicable local regulations, ethics 
committee/institutional review board regulations, and International Council for Harmonisation 
Guidelines for Good Clinical Practice. 
 
 
Coordinating Investigator’s Signature 
Date 
 
 
Coordinating Investigator’s Printed Name 
 


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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ............................................................................................. 2 
SPONSOR APPROVAL ............................................................................................................. 3 
INVESTIGATOR AGREEMENT ............................................................................................... 4 
COORDINATING INVESTIGATOR AGREEMENT ................................................................ 5 
TABLE OF CONTENTS ............................................................................................................ 6 
LIST OF IN-TEXT TABLES .................................................................................................... 10 
LIST OF IN-TEXT FIGURES .................................................................................................. 10 
1. 
PROTOCOL SUMMARY ...................................................................................... 11 
1.1. 
Synopsis ................................................................................................................. 11 
1.2. 
Schema ................................................................................................................... 18 
1.3. 
Schedule of Activities ............................................................................................. 19 
2. 
INTRODUCTION .................................................................................................. 27 
2.1. 
Study Rationale ...................................................................................................... 27 
2.2. 
Background ............................................................................................................ 28 
2.3. 
Benefit/Risk Assessment ........................................................................................ 28 
2.3.1. 
Known Potential Benefits ....................................................................................... 28 
2.3.2. 
Known Potential Risks............................................................................................ 29 
2.3.3. 
Assessment of Potential Benefits and Risks ............................................................ 31 
3. 
OBJECTIVES AND ENDPOINTS ......................................................................... 33 
4. 
STUDY DESIGN ................................................................................................... 35 
4.1. 
Overall Design ........................................................................................................ 35 
4.1.1. 
Screening/Baseline Period ...................................................................................... 35 
4.1.2. 
Treatment Period .................................................................................................... 35 
4.1.3. 
Taper Period and End of Study ............................................................................... 36 
4.2. 
Scientific Rationale for Study Design ..................................................................... 36 
4.3. 
Justification for Dose .............................................................................................. 36 
4.3.1. 
Background PK Data to Support Dose Justification ................................................ 36 
4.3.2. 
Dose Adjustments Due to Concomitant Medication Use ......................................... 37 
4.3.3. 
Treatment Duration................................................................................................. 38 
4.4. 
End of Study Definition .......................................................................................... 38 
5. 
STUDY POPULATION ......................................................................................... 39 


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5.1. 
Inclusion Criteria .................................................................................................... 39 
5.2. 
Exclusion Criteria ................................................................................................... 39 
5.3. 
Lifestyle Considerations ......................................................................................... 39 
5.3.1. 
Prohibited Medications and Substances .................................................................. 39 
5.3.2. 
Permitted Medications and Therapies ..................................................................... 40 
5.3.3. 
Rescue Medication ................................................................................................. 40 
5.4. 
Criteria for Discontinuation or Withdrawal of a Subject .......................................... 41 
5.4.1. 
Withdrawal from the Study ..................................................................................... 41 
5.5. 
Discontinuation/Withdrawal of Study Drug ............................................................ 41 
5.6. 
Lost to Follow-up ................................................................................................... 42 
6. 
STUDY DRUG ...................................................................................................... 43 
6.1. 
Study Drug Administration ..................................................................................... 43 
6.1.1. 
Description of Study Drug/Matching Placebo ......................................................... 43 
6.1.2. 
Dosing and Administration ..................................................................................... 43 
6.2. 
Preparation/Handling/Storage/Accountability ......................................................... 45 
6.2.1. 
Acquisition and Accountability ............................................................................... 45 
6.2.2. 
Study Drug Storage and Stability ............................................................................ 46 
6.2.3. 
Study Drug Preparation .......................................................................................... 46 
6.3. 
Measures to Minimize Bias ..................................................................................... 46 
7. 
STUDY ASSESSMENTS AND PROCEDURES ................................................... 47 
7.1. 
Efficacy Assessments ............................................................................................. 47 
7.1.1. 
Seizure Assessments ............................................................................................... 47 
7.1.2. 
Caregiver Diary ...................................................................................................... 47 
7.1.3. 
Caregiver Global Impression of Severity and Change Scales .................................. 48 
7.1.4. 
Clinician Global Impression of Change Scale ......................................................... 48 
7.1.5. 
Quality of Life Scales ............................................................................................. 48 
7.1.6. 
Behavior and Development Assessments ................................................................ 49 
7.1.7. 
Sleep Quality .......................................................................................................... 49 
7.1.8. 
Palatability Questionnaire ....................................................................................... 49 
7.2. 
Safety, PK, and Other Assessments......................................................................... 49 
7.2.1. 
Physical and Neurologic Examinations ................................................................... 50 
7.2.2. 
Vital Signs, Weight, and Height .............................................................................. 50 
7.2.3. 
ECG Measurements ................................................................................................ 50 


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7.2.6. 
Assessment of Suicidal Ideation.............................................................................. 51 
7.2.7. 
Clinical Laboratory Tests ........................................................................................ 51 
7.2.8. 
PK and ASM Blood Samples .................................................................................. 52 
7.2.9. 
Estimated Blood Volume Collection ....................................................................... 53 
7.2.10. 
Study Drug Compliance .......................................................................................... 55 
7.3. 
AEs and SAEs ........................................................................................................ 55 
7.3.1. 
Definition of AEs ................................................................................................... 55 
7.3.2. 
Definition of SAEs ................................................................................................. 56 
7.3.3. 
Classifications of an AE.......................................................................................... 56 
7.3.4. 
Time Period and Frequency for Event Assessment and Follow-up .......................... 57 
7.3.5. 
Reporting of Pregnancy .......................................................................................... 61 
8. 
STATISTICAL CONSIDERATIONS .................................................................... 62 
8.1. 
Sample Size Determination ..................................................................................... 62 
8.2. 
Populations for Analyses ........................................................................................ 62 
8.2.1. 
Safety Population.................................................................................................... 62 
8.2.2. 
Key Efficacy Analysis Set ...................................................................................... 62 
8.2.3. 
Secondary Efficacy Analysis Set ............................................................................ 62 
8.3. 
Statistical Analyses ................................................................................................. 62 
8.3.1. 
General Approach ................................................................................................... 62 
8.3.2. 
Analyses of Safety Endpoints ................................................................................. 62 
8.3.3. 
Analysis of the Key Efficacy Endpoint ................................................................... 63 
8.3.4. 
Analysis of Additional Efficacy Endpoints ............................................................. 64 
8.3.5. 
Handling of Missing Data ....................................................................................... 64 
8.3.6. 
Planned Interim Analysis ........................................................................................ 64 
8.3.7. 
Tabulation of Individual Participant Data................................................................ 64 
8.3.8. 
PK Analysis ............................................................................................................ 64 
9. 
SUPPORTING DOCUMENTATION..................................................................... 65 
9.1. 
Regulatory, Ethical, and Study Oversight Considerations........................................ 65 
9.1.1. 
Informed Consent Process ...................................................................................... 65 
9.1.2. 
Study Termination and Closure ............................................................................... 65 
9.1.3. 
Confidentiality and Privacy .................................................................................... 66 


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9.1.5. 
DSMB .................................................................................................................... 67 
9.1.6. 
Clinical Monitoring ................................................................................................ 67 
9.1.7. 
Quality Assurance and Quality Control ................................................................... 67 
9.1.8. 
Data Handling and Record Keeping ........................................................................ 68 
9.1.9. 
Protocol Deviations ................................................................................................ 69 
9.1.10. 
Publication and Data Sharing Policy ....................................................................... 69 
9.1.11. 
Conflict of Interest Policy ....................................................................................... 69 
9.2. 
Additional Considerations....................................................................................... 70 
9.3. 
List of Abbreviations .............................................................................................. 71 
10. 
REFERENCES ....................................................................................................... 73 
11. 
APPENDICES ........................................................................................................ 76 
APPENDIX A. SEIZURE DEFINITIONS.............................................................................. 77 
APPENDIX B. CAREGIVER GLOBAL IMPRESSION OF SEVERITY SCALES ............... 78 
APPENDIX C. CAREGIVER GLOBAL IMPRESSION OF CHANGE SCALES .................. 79 
APPENDIX D. CLINICIAN GLOBAL IMPRESSION OF CHANGE SCALES .................... 82 
APPENDIX E. SLEEP QUALITY QUESTIONS ................................................................... 83 
APPENDIX F. CAREGIVER IMPRESSION OF STUDY DRUG PALATABILITY ............. 84 
APPENDIX G. LIST OF PROHIBITED CONCOMITANT MEDICATIONS........................ 85 
 
 
 
 
 
 
 


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LIST OF IN-TEXT TABLES 
Table 1 
Schedule of Activities, Baseline and Treatment Period Up to 1 Year ...................... 19 
Table 2 
Schedule of Activities, Long-term Treatment Period (up to 3 Years), and 
Taper and Follow-up Visits ..................................................................................... 23 
Table 3 
Titration Scheme .................................................................................................... 44 
Table 4 
Clinical Laboratory Tests ........................................................................................ 51 
 
 
 
 
 
LIST OF IN-TEXT FIGURES 
Figure 1 
Study Design Schematic ......................................................................................... 18 
Figure 2 
Pediatric Systemic Exposure Relative to Historical Adult Data ............................... 37 
 
 


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1. 
PROTOCOL SUMMARY 
1.1. 
Synopsis 
Protocol Title: 
An Open-label Extension Study of XEN496 in Pediatric Subjects With 
KCNQ2 Developmental and Epileptic Encephalopathy 
Protocol Number: 
XPF-009-302 
Protocol Identifier: 
EPIK OLE 
Phase: 
Phase 3 
Study Drug: 
XEN496: Immediate-release, multi-particulate sprinkle capsule formulation 
of ezogabine (retigabine) for pediatric subjects. 
Placebo: Matching capsules containing inactive ingredients (used only 
during the double-blind transition/titration period). 
The capsules are meant to be opened and the contents dispersed into soft 
foods or liquids for oral administration 
 
 
Indication: 
Treatment of seizures in pediatric subjects with KCNQ2 developmental and 
epileptic encephalopathy (KCNQ2-DEE). 
Study Description: 
An international, multicenter, open-label extension (OLE) study to assess 
the long-term safety, tolerability, and efficacy of XEN496 in pediatric 
subjects with KCNQ2-DEE who participated in the primary efficacy and 
safety study (XPF-009-301). 
Objectives: 
Primary Objective: 
• 
To assess the long-term safety and tolerability of XEN496 in pediatric 
subjects with KCNQ2-DEE who had participated in the primary study 
(XPF-009-301). 
Secondary Objectives: 
• 
To evaluate the intrasubject efficacy of XEN496 in reducing seizure 
frequency compared to prior placebo treatment in pediatric subjects 
with KCNQ2-DEE who were previously randomized to receive placebo 
in the primary double-blind Phase 3 study (XPF-009-301). 
• 
To assess the long-term effect of XEN496 on seizure reduction in 
pediatric subjects treated with XEN496. 
• 
To evaluate Caregiver Global Impression of Severity (CaGI-S) and 
Caregiver Global Impression of Change (CaGI-C) scores in pediatric 
subjects with KCNQ2-DEE. 
• 
To assess neurocognitive development and behavior after dosing with 
XEN496 in pediatric subjects with KCNQ2-DEE. 
• 
To evaluate the investigator’s global impression of the change in the 
subject’s overall condition, assessed using the Clinical Global 
Impression of Change (CGI-C) scale. 
• 
To evaluate the use of rescue medication and change in background 
antiseizure medications (ASM). 


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To assess the impact of XEN496 on the quality of life of caregivers and 
subjects with KCNQ2-DEE. 
• 
To evaluate the plasma concentrations of ezogabine and N-acetyl 
metabolite of retigabine (ezogabine) (NAMR). 
Study Population: 
Approximately 40 pediatric subjects diagnosed with KCNQ2-DEE who 
participated in the primary study (XPF-009-301). 
Study Duration: 
Subjects will undergo: 
• 
Screening/Baseline period – subjects will undergo eligibility 
assessment at Visit 22 or early termination in the primary study 
(XPF-009-301). 
• 
Treatment period – 36 months: 
o Blinded transition/titration period – 24 days. 
o Open-label period – approximately 35 months. 
• 
Taper period – Up to 15 days. 
Subjects who discontinue or complete the study treatment will be 
required to taper off study drug over a period of up to 15 days. 
• 
Follow-up – Approximately 4 weeks after subjects have tapered off 
study drug. 
Total study duration per subject is estimated to be 37 months. 
Study Design: 
Study Type: Interventional. 
Estimated Enrollment: Approximately 40 subjects. 
Intervention: Single group, open-label treatment with XEN496. 
Description: This is an open-label, long-term extension study of XEN496 
for the treatment of seizures in subjects with KCNQ2-DEE, that will be 
open to eligible subjects who participated in the primary study, 
XPF-009-301. The primary objective is to assess the long-term safety of 
XEN496. 
The study includes a screening/baseline visit to assess eligibility. A 
double-blind transition/titration period will be used to maintain blinding to 
the treatment allocation in the primary study (XPF-009-301). 
After completion of the blinded transition/titration period, subjects will 
continue to receive the study drug at their optimal dose for approximately 
35 months. 
Screening/Baseline: 
Screening/baseline procedures and assessments will be conducted at 
Visit 22 or early termination in the primary study (XPF-009-301); 
procedures and assessments in addition to those required at these visits may 
be conducted in order to confirm eligibility for the OLE study. 
Treatment Period: 
Blinded Transition/Titration Period: 
Subjects who received XEN496 in the primary study will continue to 
receive XEN496 at the same dose throughout the OLE. 
Subjects allocated to placebo in the primary study will be required to begin 
a titration of XEN496 
 


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The transition/titration will be performed in a blinded manner to maintain 
the blind to the treatment arm from the primary study. 
Open-label Period: 
Following the transition/titration period, subjects will continue open-label 
treatment at their optimal dose of XEN496 for approximately 35 months. 
Taper Period and End of Study: 
At the end of the treatment period, subjects will be required to taper off 
study drug over a period of up to 15 days. 
Subjects who discontinue the study early will be required to enter into the 
taper period at that time and will be expected to complete the end of study 
follow-up safety monitoring schedule. 
Subjects will be monitored for safety for 28 days after the last dose of study 
drug has been administered. 
Criteria for Subject 
Selection: 
Criteria for Inclusion: 
To be eligible to participate in the study, an individual must meet all of the 
following criteria: 
1. Subject completed participation as defined in the primary study, 
XPF-009-301. A subject who withdraws from the primary study due to 
meeting protocol-specified worsening criteria will be considered as 
having completed participation in the primary study. 
2. The caregiver is willing and able to comply with diary completion, visit 
schedule, and study drug administration requirements. 
3. Subject’s caregiver achieved a minimum of 85% compliance with daily 
diary completion during both baseline and the double-blind period of 
the primary study. 
Criteria for Exclusion: 
Any subject who meets any of the following criteria will not qualify for 
entry into the study: 
1. Any adverse event (AE) or serious adverse event (SAE) during 
Study XPF-009-301, which in the opinion of the investigator and 
sponsor’s medical monitor, would preclude the subject’s entry into the 
OLE. 
2. A clinically significant condition or illness, or symptoms other than 
those resulting from KCNQ2-DEE, present at screening/baseline that, 
in the opinion of the investigator, would pose risk to the subject if s/he 
were to enter the study. 
3. Any conditions that were specified as exclusion criteria in the primary 
study (XPF-009-301). 
4. It is anticipated that the subject will require treatment with at least one 
of the disallowed medications during the study. 
5. 
 
 
 


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Treatment Allocation: 
All subjects rolling over into the OLE study will receive active treatment 
with XEN496. Subjects will undergo a blinded transition/titration period, 
regardless of their treatment allocation in the primary study (XPF-009-301). 
Dose Administration 
and Discontinuation: 
Dose Administration: 
XEN496 is supplied as sprinkle capsules at 3 dose strengths of 
 
 Capsules in dose strengths of 
 will be dispensed 
when subjects complete their transition or titration period. 
The daily dose of XEN496 is calculated based on body weight and should 
be administered orally 3 times daily (TID) in equally divided doses (as 
supplied by the pharmacy). The entire contents of the capsules containing 
XEN496 
 
of a soft food or liquid prior to ingestion. 
 
 
 
Treatment Period: 
Blinded Transition/Titration Period: 
The treatment period begins with a dose transition/titration period. 
Subjects who received XEN496 in the preceding study will continue to 
receive XEN496 at the same dose, in a blinded manner, without any further 
titration. 
Subjects allocated to placebo in the preceding study, 
 
 
 
 
The following dose titration scheme is approximate. The final dose and 
number of capsules using the weight-based dosing are detailed in the 
pharmacy manual. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The investigator will be blinded during the transition/titration period. 
Assuming no moderate to severe treatment-related AEs occur, the subject’s 
dose will be escalated to the next dose level during titration according to the 
dosing regimen. 
The maximum dose will not exceed 
 
 


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Open-label Period: 
The optimally-tolerated dose level established during the transition/titration 
period will be maintained throughout the duration of the open-label period 
unless dose adjustment is required. 
The investigator will assess the subject’s tolerability and AE profile 
throughout the treatment period. 
 
 
 
 
 
 
 
Dose Taper Period: 
Subjects who complete the study or exit the study early should have the 
dose reduced in a stepwise manner 
 that 
were used during titration, but in reverse order. 
Outcome Measures: 
Safety Endpoints: 
• 
Severity and frequency of AEs and SAEs; clinically significant changes 
in laboratory tests, vital signs, electrocardiograms (ECGs), physical and 
neurologic examinations, 
 
 
Key Efficacy Endpoint: 
• 
Change in monthly countable motor seizure frequency, comparing the 
first 15 weeks of XEN496 treatment in the OLE study to the seizure 
frequency reported during treatment in the preceding primary study 
(XPF-009-301), among only those subjects who were randomized to 
the placebo arm in the primary study (XPF‑009-301). 
Additional Endpoints: 
• 
Change from pre-randomization baseline in the previous study over 
time based on response categories (<25%, 25 to <50%, 50 to <75%, 75 
to <100%, 100%), based on estimated seizure frequency every 
3 months during the OLE period. 
• 
Percent change from baseline in countable motor seizure frequency, 
relative to pre-randomization baseline of the previous study 
(XPF-009-301), assessed over time every 3 months during the OLE. 
• 
Percent change from baseline in countable motor seizure frequency, 
relative to pre-randomization baseline of the previous study 
(XPF-009-301), for every 3 months based on combined data from both 
XPF-009-301 and the OLE, by the treatment group in the previous 
study. 


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• 
Change over time in CaGI-S scores for the subject’s seizures and 
overall condition. 
• 
Change over time in CaGI-C scores for the subject in the following 
domains: overall condition, seizures, behavior, alertness, motor skills, 
visual function, and communication. 
• 
Change over time in neurocognitive development based on the Bayley 
Scales of Infant and Toddler Development, Third Edition (BSID-III). 
• 
Change over time in adaptive behavior based on the Adaptive Behavior 
Assessment System, Third Edition (ABAS-3). 
• 
Change over time in CGI-C scores for the subject’s seizures and overall 
condition. 
• 
Use of rescue medication. 
• 
Use of all concomitant medications including treatments used for 
seizure control. 
• 
Change in quality of life of subjects with KCNQ2-DEE, based on the 
Pediatric Quality of Life Inventory (PedsQL). 
• 
Change in quality of life of subjects with KCNQ2-DEE, based on the 
Pediatric Quality of Life Inventory, Family Impact Module 
(PedsQL-FIM). 
• 
Plasma concentrations of ezogabine and NAMR. 
Statistical 
Considerations: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Sample Size 
Determination: 
Approximately 40 subjects may be included in the study based on the 
number of subjects who could roll over from Study XPF-009-301. 
 


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1.2. 
Schema 
Figure 1 
Study Design Schematic 
 
 
 been treated for at least 15 weeks in the open-label extension. 
 
 


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1.3. 
Schedule of Activities 
The Schedule of Activities is presented in 2 tables. Table 1 includes the baseline and treatment period up to 1 year, and Table 2 
includes the long-term treatment period (up to 3 years), and taper and follow-up visits. 


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Protocol XPF-009-302 
SAP
STATISTICAL ANALYSIS PLAN
Available upon request.

SAP_002.pdf: 
Statistical Analysis Plan 
Statistical Analysis Plan
Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
      Page 1 of 47
Protocol Title:
AN OPEN-LABEL EXTENSION STUDY OF XEN496 IN 
PEDIATRIC SUBJECTS WITH KCNQ2 DEVELOPMENTAL 
AND EPILEPTIC ENCEPHALOPATHY
Protocol Number:
XPF-009-302
Protocol Version, Date
3.0, 09 May 2022
Document Version, Date:
Final 1.0, 04MAY2023
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Statistical Analysis Plan 
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Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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SIGNATURE PAGE
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Statistical Analysis Plan 
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Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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REVISION HISTORY
Version/Date
Version name
Changes implemented
Version 1.0/
04May2023
Initial 
approved 
version
N/A
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Statistical Analysis Plan 
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Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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TABLE OF CONTENTS
SIGNATURE PAGE............................................................................................................. 2
REVISION HISTORY .......................................................................................................... 3
TABLE OF CONTENTS ...................................................................................................... 4
LIST OF ABBREVIATIONS ............................................................................................... 6
1
INTRODUCTION........................................................................................................... 8
2
STUDY OBJECTIVES AND ENDPOINTS .................................................................. 9
3
STUDY DESIGN .......................................................................................................... 12
3.1
General study design ............................................................................................ 12
3.2
Randomization and blinding................................................................................. 13
3.3
Study treatments and assessments ........................................................................ 13
4
SAMPLE SIZE Determination...................................................................................... 23
5
ANALYSIS POPULATIONS....................................................................................... 24
5.1
Enrolled Set .......................................................................................................... 24
5.2
Safety Set.............................................................................................................. 24
5.3
Key Efficacy Analysis Set.................................................................................... 24
5.4
Secondary Efficacy Analysis Set.......................................................................... 24
6
Statistical Considerations and analysis.......................................................................... 25
6.1
Derived Variables................................................................................................. 25
6.1.1
Efficacy Variables .................................................................................... 27
6.1.1.1 Seizure frequency ..................................................................................... 27
6.2
Handling of missing data and outliers .................................................................. 29
6.2.1
Missing data analysis methods ................................................................. 29
6.2.2
Handling of missing or incomplete dates ................................................. 29
7
STATISTICAL METHODS.......................................................................................... 31
7.1
General statistical conventions............................................................................. 31
7.2
Subject disposition................................................................................................ 31
7.3
Protocol deviations ............................................................................................... 32
7.4
Demographics and background characteristics .................................................... 32
7.4.1
Demographics........................................................................................... 32
7.4.2
Baseline disease characteristics................................................................ 32
7.4.3
Concomitant medications ......................................................................... 33
7.4.4
Concomitant procedures........................................................................... 33
7.5
Extent of exposure................................................................................................ 33
7.5.1
Treatment duration ................................................................................... 33
7.5.2
Treatment compliance .............................................................................. 33
7.6
Efficacy analyses .................................................................................................. 33
7.6.1
Analysis of key efficacy endpoint ............................................................ 33
7.6.2
Analysis of additional efficacy endpoints ................................................ 34
7.6.2.1 To assess the long-term effect of XEN496 on seizure reduction in 
pediatric subjects treated with XEN496................................................... 34
7.6.2.2 To evaluate Caregiver Global Impression of Severity (CaGI-S) and 
Caregiver Global Impression of Change (CaGI-C) scores....................... 35
7.6.2.3 To assess neurocognitive development and behavior............................... 35
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Statistical Analysis Plan 
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Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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7.6.2.4
-C) .......... 36
7.6.2.5 Rescue medication usage.......................................................................... 36
7.6.2.6 To assess the impact of XEN496 on the quality of life............................ 36
7.7
Safety analyses ..................................................................................................... 37
7.7.1
Adverse events.......................................................................................... 37
7.7.2
Clinical laboratory evaluations................................................................. 38
7.7.3
Vital signs................................................................................................. 39
7.7.4
Physical examinations .............................................................................. 39
7.7.5
Electrocardiograms................................................................................... 39
7.7.6
Other safety assessments .......................................................................... 40
7.8
Interim analysis .................................................................................................... 40
8
CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL..................... 41
9
REFERENCES .............................................................................................................. 42
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Statistical Analysis Plan 
Statistical Analysis Plan
Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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1
INTRODUCTION
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of the 
statistical methods, data derivations and data displays for study protocol XPF-009-302
Version 3.0, 
open-label extension study of XEN496 in pediatric subjects with KCNQ2 
table of contents and templates for the tables, figures and listings (TFLs) will be produced 
in a separate document.
Any deviations from this SAP will be described and justified in the Clinical Study Report 
(CSR).
The preparation of this SAP has been based on International Conference on Harmonization 
(ICH) E3 and E9 guidelines.
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Statistical Analysis Plan 
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Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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3
STUDY DESIGN
3.1
General study design
This is a Phase 3, open-label, long-term extension study to evaluate the safety, tolerability, 
and efficacy of XEN496 administered as adjunctive therapy in pediatric subjects with 
KCNQ2-DEE who participated in the primary study, XPF-009-301.
Approximately 40 subjects may be included in the study based on the anticipated number of
subjects who could roll over from Study XPF-009-301.
Subjects will undergo the following:
Screening/Baseline period Subjects will undergo eligibility assessment at Visit 22 
or early termination in the primary study (XPF-009-301).
Treatment period 36 months:
o
Blinded transition/titration period
o
Open-label period approximately 35 months.
Subjects who received XEN496 in the primary study will continue to receive 
XEN496 at the same dose throughout the OLE.
Subjects allocated to placebo in the primary study will be required to begin a titration 
of XEN496
 
Taper period 
Subjects who discontinue or complete the study treatment will be required to taper 
off study drug 
 The actual duration of the taper period 
Follow-up Approximately 4 weeks after subjects have tapered off of study drug.
Total study duration per subject is estimated to be 37 months.
The Study Design Schematic is presented in Figure 1.
Figure 1: Study Design Schematic
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Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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The optimally-tolerated dose level established during the transition/titration period will be
maintained throughout the duration of the open-label period unless dose adjustment is 
required.
A detailed description of procedures and assessments to be conducted during this study is 
summarized in the Scheduled of Study Assessments in Table 2 and Table 3 below.
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Statistical Analysis Plan (SAP)
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Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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4
SAMPLE SIZE DETERMINATION
No formal sample size calculation has been performed. Only those subjects who have 
completed the previous study, XPF-009-301, are eligible to be enrolled into this study. 
Therefore, the expected total sample size will be up to approximately 40 subjects.
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Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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5
ANALYSIS POPULATIONS
5.1
Enrolled Set
Enrolled set include all subjects who signed the informed consent form.
5.2
Safety Set
 
5.3
Key Efficacy Analysis Set 
The key efficacy analysis set includes those subjects who were treated with placebo in the 
preceding primary study (XPF-009-301) and switched to XEN496 treatment in the current 
study, with at least 4 weeks of evaluable seizure data in both study periods.
5.4
Secondary Efficacy Analysis Set
The secondary efficacy analysis set includes those subjects who were treated in both the
preceding primary study (XPF-009-301) and the current OLE study, with at least 1 evaluable
seizure data in both study periods.
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Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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Percent change of average monthly seizure frequency will be derived using the below 
formula where 
is defined as above and 
refers to the comparator period appropriate for the endpoint (eg. placebo period for the key 
efficacy endpoint and the pre-randomization baseline period for other efficacy endpoints):
6.2
Handling of missing data and outliers
6.2.1
Missing data analysis methods
The key efficacy endpoint of seizure frequency will be derived from the days with non-
missing seizure data as described in Section 6.1.1. To assess the impact of missing data due 
to early dropout, sensitivity analysis incorporating missing data multiple imputations with 
both missing at random (MAR) and missing not at random (MNAR) mechanisms. Details of 
the analysis will be specified in the analysis section 7.6.1..
6.2.2
Handling of missing or incomplete dates
Missing or partial AE onset dates and times will be imputed so that if the partial AE onset 
date/time information does not indicate that the AE started prior to treatment or after the 
treatment emergent adverse event (TEAE) period, the AE will be classified as treatment-
emergent. These data imputations are for categorization purpose only and will not be used 
in listings. No imputation is planned for date/time of AE resolution.
No imputation for medication start/end dates or times will be performed. Partial dates will 
be used to determine whether concomitantly. If a medication date or time is missing or 
partially missing date cannot be determined whether it was taken concomitantly, those 
medications will be considered as concomitant medication.
Imputation rules for missing or partial AE start date are defined below:
1) If only Day of AE start date is missing: 
If the AE start year and month are the same as that for the OLE first dose date, then 
impute the AE start day as the day of OLE first dose date, if the full (or partial) AE 
end date is NOT before the first dose date or AE end date is missing: otherwise, 
impute the AE start day as 1.
Otherwise, impute the AE start day as 1.
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Statistical Analysis Plan (SAP)
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Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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2) If Day and Month of AE start date are missing:
If AE start year is equal to first dose year, then impute the AE start Month and Day 
as the Month and Day of OLE first dose date, if the full (or partial) AE end date is 
NOT not before the first dose date or AE end date is missing; otherwise, impute the 
AE start Month as January and the Day as 1.
3) If AE start date is missing:
If the AE start date is completely missing, then query site with no imputation.
Also compare the full (or partial) AE end date to the first dose date. If the AE end 
date is before the first OLE dose date, then the AE should be considered as a pre OLE 
treatment AE. 
Otherwise, the AE will be considered as TEAE.
Compare the imputed AE start date with TE period to determine whether the AE is pre OLE 
treatment AE or TEAE.
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Statistical Analysis Plan (SAP)
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Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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7
STATISTICAL METHODS
7.1
General statistical conventions
All statistical procedures will be completed using SAS GRID Linux/SAS Studio version 9.4.
Unless otherwise stated, all statistical testing will be two-sided and will be performed using 
a significance (alpha) level of 0.05. Two-sided 95% confidence intervals (CI) will be 
provided when relevant.
Continuous variables will be summarized using descriptive statistics, including number of 
subjects (n), mean, geometric mean (for efficacy endpoints only), first quartile (Q1), median, 
third quartile (Q3), standard deviation (SD), minimum and maximum. 
Categorical variables will be summarized using frequency counts and percentages in each 
category. The denominator for all percentages will be the number of subjects in that 
treatment group within the population of interest, unless otherwise noted. Percentages will 
be rounded to one decimal place.
For summary purposes, baseline will be defined as the last available OLE pre-dose value; 
all summaries will be presented by treatment group assigned in the double blind study (XPF-
009-301) and overall, unless otherwise specified. 
XEN496 Only
(Subjects who received XEN496 in the primary study and continue to receive 
XEN496 at the same dose throughout the OLE)
Placebo to XEN496
(Subjects allocated to placebo in the primary study and received XEN496 in OLE)
Total
All subject data, will be presented in individual subject data listings. Unless otherwise stated, 
unscheduled visit results will be included in date/time chronological order, within subject 
e will be stated on each 
listing. Unless otherwise stated, data listings will be based on all enrolled set.
7.2
Subject disposition
Subject disposition information will be summarized by treatment group in OLE period and 
overall. The disposition summary will include the number and percentage of subjects 
meeting the following criteria:
Screened
Screen failed
Received a dose in OLE period 
Completed treatment 
Discontinued treatment
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Statistical Analysis Plan (SAP)
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Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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Reasons for discontinued treatment
Completed the study
Completed the Taper period
Completed Follow Up 
Discontinued from the study
Reasons for discontinuation from study
The number of subjects who took a dose in OLE period will be used as the denominator for 
the percentage calculation. Subject disposition will be listed for subjects who signed 
informed consent form. Details of eligibility criteria for enrollment will be listed separately.
The number and percentage of subjects in each analysis set and reason for exclusion will 
also be tabulated separately. Population membership details will be listed, including reason 
for exclusion from each population
7.3
Protocol deviations
Important protocol deviations identified will be summarized based on safety set.
A listing will include all important deviations identified based on data recorded and/or 
protocol deviation logs.
impact due to Corona Virus Disease of 2019 (COVID-19).
7.4
Demographics and background characteristics
7.4.1
Demographics
Demographic variables age (months), adjusted age (months), at baseline will be summarized 
descriptively. Age category (<2 years, 
and country will be 
summarized using count and percentage.
7.4.2
Baseline disease characteristics
The following baseline variables from the double blind study (XPF-009-301) will be 
summarized using descriptive statistics or counts and percentage.
Subjects experience >= 1 seizure per day in the month prior to screening
Number of seizures per month (28 days) prior to screening
Diagnostic KCNQ2 genetic testing details
o
Zygosity
o
Genetic test classification
Subjects with vagus nerve stimulation therapy (Yes/No)
Pre-study seizure type ( Pre-study Seizure Type and Description CRF page)
Listings will be provided for all information captured in CRF for seizure diagnosis and 
treatment history, diagnostic KCNQ2 genetic testing, vagus nerve stimulation therapy, pre-
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Statistical Analysis Plan (SAP)
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Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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study seizure type and description.
7.4.3
Concomitant medications
Medications will be coded to a preferred term and an Anatomic Therapeutic Classification 
(ATC) code by using the latest available version of the World Health Organization Drug 
Dictionary Enhanced (WHODDE). 
Concomitant medications: are defined as any medications taken between first dose of study 
treatment (inclusive) in OLE and last dose of study treatment (including taper period). If any 
medication started prior to first dose in OLE and are ongoing or ended after first dose in 
OLE are also considered as concomitant.
Concomitant medications will be summarized descriptively using frequency tables by ATC 
class 2 and preferred name.
Listing will be provided for concomitant medication.
7.4.4
Concomitant procedures
Concomitant procedures (Surgical or Non-Surgical) will be presented in a listing only.
7.5
Extent of exposure
7.5.1
Treatment duration
Duration of study drug (in days) in OLE will be calculated as: last dose date
first dose 
date in OLE+ 1 day, regardless of study drug interruption.
Duration of study drug exposure and total dose (sum of all dose administered) administered 
will be summarized descriptively using safety set.
7.5.2
Treatment compliance
Study drug compliance based on the number of capsules taken will be calculated as:
Descriptive summary for study drug compliance using safety set. They will also be 
,
Study drug administration details will be listed.
7.6
Efficacy analyses
7.6.1
Analysis of key efficacy endpoint
Analysis of the key efficacy endpoint based on key efficacy analysis set.
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Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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The difference between XEN496 and placebo in monthly seizure frequency among subjects 
who were randomized to placebo in the main study will be analyzed using a Wilcoxon 
signed-rank test with 2-sided significance level of 5%. The estimated pseudo-median intra-
subject difference in seizure frequency will be provided with corresponding 95% CI (2-
sided) based on Hodges-Lehmann method.
 
.
Descriptive summary will be provided for average monthly (4-week) seizure frequency 
collected from motor seizures described above. Individual listings will also be provided.
7.6.2
Analysis of additional efficacy endpoints
Analyses of additional secondary efficacy endpoints will primarily be descriptive based on 
the secondary efficacy analysis set.
For the summary of data from the OLE only, a combined treatment group including those 
subjects treated in OLE will be included. For the summary of endpoints with a combined 
database from both the primary study (XPF-009-301) and the OLE study, the data will be 
presented by treatment group in the primary study (XPF-009-301). Data after switching from 
placebo to XEN496 will be clearly identified.
7.6.2.1 To assess the long-term effect of XEN496 on seizure reduction in pediatric 
subjects treated with XEN496
Change from pre-randomization baseline (double blind baseline, refer Section 7.1) 
in the previous study over time based on response categories (<25%, 25 to <50%, 50 
to <75%, 75 to <100%, 100%), based on estimated seizure frequency every 3 months 
during the OLE period. Proportion of subjects achieving a reduction in 3 months (90
day) seizure frequency from baseline of <25%, 25% to <50%, 50% to <75%, 75% to 
<100%, and 100% will be summarized using count and percentage. (refer section 
6.1.1 for details).
Descriptive summary will be given for percent change from baseline in countable 
motor seizure frequency, relative to pre-randomization baseline of the previous study 
(XPF-009-301), assessed over time every 3 months during the OLE.
Descriptive summary will be provided for percent change from baseline in countable
motor seizure frequency, relative to pre-randomization baseline of the previous study 
(XPF-009-301), for every 3 months based on combined data from both XPF-009-301 
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Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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7.7.2
Clinical laboratory evaluations
Observed and change from OLE baseline clinical laboratory test data will be summarized 
descriptively for each scheduled visit and presented based on the safety set. 
Shift from baseline to post-baseline laboratory findings at each visit in normal range criteria 
(Low, Normal, High) will also be summarized for chemistry and hematology tests. 
The incidence of potentially clinically significant abnormalities (PCSA) for liver function 
(Table 4) for each scheduled visit will be summarized. 
Table 4: Potentially Clinically Significant Abnormality (PCSA) Liver Abnormality 
Criteria
Parameter
PCSA Criteria
Chemistry
Alanine transaminase (ALT) or Aspartate transferase
(AST) >=3x Upper limit of normal (ULN)
ALT or AST >=5xULN
ALT or AST >=8xULN
ALT or AST >=3xULN and <5xULN, with Baseline 
>=2xULN
ALT or AST >=5xULN and <8xULN, with Baseline 
>=2xULN
ALT or AST >=5xULN with Baseline >=2xULN
Alkaline Phosphatase >=1.5xULN
Total Bilirubin >=2xULN
ALT >=3xULN and Total Bilirubin >=2xULN
Any Chemistry Test
Hematology
White blood cells (WBC) <2.0 and >20,000 103
cells/uL
Hgb:
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Version: Final 1.0 Date: 04MAY2023
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Parameter
PCSA Criteria
       Age 30-60 days: Hgb < 7 g/dL
       Age 61 days to 6 years: Hgb <9 g/dL
Platelets (PLT) <50 x 10^3 cells/uL
Any Hematology Test
A listing will be provided for clinical laboratory test data. The listing will include normal 
ranges and clinical laboratory values that are outside the normal ranges and potentially 
clinically significant abnormalities will be flagged in the listing.
7.7.3
Vital signs
Observed and changes from OLE baseline for vital sign measurements will be summarized 
at each scheduled visit using descriptive statistics. In addition, summaries will be provided 
for the potentially clinicallly importance categories as presented below.
Table 5: Potentially Clinically Significant Vital Signs Abnormality Criteria
Parameter
Criterion
Systolic Blood Pressure (mmHg)
> ULN and increase of > 30
< Lower limit of normal (LLN) and 
decrease of > 20
Diastolic Blood Pressure (mmHg)
> ULN and increase of > 20 
< LLN and decrease of > 15 
Pulse Rate (bpm)
>= ULN 
<= LLN 
Listings will be provided for vital sign data, and potentially clinically significant 
abnormalities will be flagged in the listing.
7.7.4
Physical examinations
All physical examination data will be listed using safety set.
7.7.5
Electrocardiograms
Observed and changes from OLE baseline of continuous ECG measurements will be 
summarized by treatment group and age groups (1 to 12 months and >12 to 84 months) at 
each scheduled visit. Additional summaries will be provided for ECG interpretation and will 
be summarized using frequency tables. Shift from baseline to post-baseline will also be 
provided for the ECG interpretation.
Potentially clinically significant abnormality categories listed below will be summarized 
using count and percentage.
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Protocol Number: XPF-009-302
Version: Final 1.0 Date: 04MAY2023
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8
CHANGES TO PLANNED ANALYSIS FROM STUDY PROTOCOL
 
 
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Version: Final 1.0 Date: 04MAY2023
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9
REFERENCES
1. ICH Topic E3: Structure and Content of Clinical Study Reports (CPMP/ICH/137/95-
adopted December 1995).
2. ICH Topic E9: Statistical Principles for Clinical Trials (CPMP/ICH/363/96 
adopted March 1998).
 
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10
APPENDIX
Appendix 1: Pediatric Quality of Life (PedsQL) Inventory  scale score
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Version: Final 1.0 Date: 04MAY2023
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DESCRIPTION OF THE QUESTIONNAIRE (Ages 2-4 year)
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Version: Final 1.0 Date: 04MAY2023
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DESCRIPTION OF THE QUESTIONNAIRE (Ages 5-7 year)
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Note: Domain scores physical functioning, physical symptoms, emotional functioning, 
social functioning, cognitive and school functioning need to be derived according to the 
age group where applicable.
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Appendix 2: Pediatric Quality of Life Inventory- Family Impact scale (PedsQL-FIM)
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