Clinical trial NCT04639310
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
Sponsor: Xenon Pharmaceuticals Inc.
Start date: 2021-03-29; Completion date: 2023-05-16
Enrollment: 8 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
To investigate the potential antiseizure effects of adjunctive XEN496 (ezogabine) compared with placebo in children with KCNQ2 Developmental and Epileptic Encephalopathy (KCNQ2-DEE).

Detailed description:
The EPIK Phase 3 clinical trial is designed as a randomized, double-blind, placebo-controlled, multicenter study targeting to enroll approximately 40 pediatric subjects (aged from 1 month to less than 6 years) with documented genetic evidence consistent with a diagnosis of KCNQ2 Developmental and Epileptic Encephalopathy (KCNQ2-DEE). After screening, subjects will enter a baseline period before being randomized to receive either XEN496 (ezogabine) or placebo, added to their existing antiseizure medications (ASMs), for 12 weeks (maintenance), once a titration period of up to 24 days is complete. At the end of the maintenance phase, eligible subjects will have the opportunity to qualify for and participate in the separate open-label extension (OLE) study and receive XEN496 or, should they choose to exit the study, will undergo a dose taper period of up to 15 days and 4-week follow-up.

Arms: arm 1: 24-day dose titration period to a top dose of 21 mg/kg/day. Subjects continue at the top dose, or the highest tolerated dose up to the top dose, for 12-week maintenance period. If the subject does not immediately enter into the separate open-label extension (OLE) study, the maintenance period will be followed by a 15-day taper period. arm 2: To maintain the blinded aspect of the study, subjects will be titrated on placebo over the 24-day period and remain at this dose for the 12-week maintenance period. If the subject does not immediately enter into the separate OLE study, the maintenance period will be followed by a 15-day taper period.
Interventions: intervention 1: XEN496 intervention 2: Placebo
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 TID. intervention 2: Placebo 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 TID.

Protocol documents:
Prot_SAP_000.pdf: 
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A Phase 3 Study of Adjunctive XEN496 in Pediatric Subjects With KCNQ2 Developmental 
and Epileptic Encephalopathy 
 
 
Protocol Number: XPF-009-301 
IND Number: 138144 
Eudra CT Number: 2020-002396-35 
Clinical Study Identifier: EPIK 
 
Compound: XEN496; Ezogabine (USAN); Retigabine (INN) 
 
Sponsor: Xenon Pharmaceuticals Inc. 
200-3650 Gilmore Way 
Burnaby, British Columbia 
V5G 4W8 
Canada 
 
Version Number: 5.0 
10 Nov 2022 
 
 
 
 
 
 
 
 
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 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, ICH-GCP guidelines, and 
applicable regulatory requirements. 
The protocol, ICF(s), recruitment materials, and all subject materials will be submitted to the 
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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INVESTIGATOR AGREEMENT 
STUDY TITLE: A Phase 3 Study of Adjunctive 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 will provide copies of this protocol and access to all information 
furnished by Xenon Pharmaceuticals Inc. (Xenon) to study personnel under my supervision. I 
will discuss this material with them to ensure they are fully informed about the study drug and 
study procedures. I will let them know that this information is confidential and proprietary to 
Xenon and that it may not be further disclosed to third parties. 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 conduct this study in full accordance with applicable local regulations, EC/IRB 
regulations, and ICH-GCP guidelines. 
 
 
 
 
Investigator’s Signature 
 
Date 
 
 
 
 
Investigator’s Printed Name 
 
 




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TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE .................................................................................................2 
INVESTIGATOR AGREEMENT...................................................................................................3 
COORDINATING INVESTIGATOR AGREEMENT ...................................................................4 
1. 
PROTOCOL SUMMARY ..........................................................................................11 
1.1. 
Synopsis ......................................................................................................................11 
1.2. 
Schema ........................................................................................................................20 
1.3. 
Schedule of Assessments ............................................................................................21 
2. 
INTRODUCTION ......................................................................................................29 
2.1. 
Study Rationale ...........................................................................................................29 
2.2. 
Background .................................................................................................................30 
2.3. 
Benefit/Risk Assessment ............................................................................................30 
2.3.1. 
Known Potential Benefits ...........................................................................................30 
2.3.2. 
Known Potential Risks ...............................................................................................31 
2.3.3. 
Assessment of Potential Benefits and Risks ...............................................................33 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................34 
4. 
STUDY DESIGN .......................................................................................................36 
4.1. 
Overall Design ............................................................................................................36 
4.1.1. 
Screening/Baseline Period ..........................................................................................37 
4.1.1.1. 
Screening ....................................................................................................................37 
4.1.1.2. 
Establishment of Baseline Seizure Frequency ............................................................37 
4.1.2. 
Randomization ............................................................................................................38 
4.1.3. 
Treatment Period ........................................................................................................38 
4.1.3.1. 
Dose Titration .............................................................................................................38 
4.1.3.2. 
Maintenance ................................................................................................................38 
4.1.4. 
Taper Period and End of Study ...................................................................................38 
4.2. 
Long-term OLE ..........................................................................................................38 
4.3. 
Scientific Rationale for Study Design ........................................................................39 
4.4. 
Justification for Dose ..................................................................................................39 
4.4.1. 
Background PK Data to Support Dose Justification ...................................................39 
4.4.2. 
Dose Adjustments Due to Concomitant Medication Use ...........................................40 
4.4.3. 
Dose Duration .............................................................................................................41 


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4.5. 
End of Study Definition ..............................................................................................41 
5. 
STUDY POPULATION .............................................................................................42 
5.1. 
Inclusion Criteria ........................................................................................................42 
5.2. 
Exclusion Criteria .......................................................................................................42 
5.3. 
Randomization Criteria ...............................................................................................44 
5.3.1. 
Eligibility Confirmation ..............................................................................................44 
5.4. 
Lifestyle Considerations .............................................................................................44 
5.4.1. 
Prohibited Medications and Substances .....................................................................44 
5.4.2. 
Permitted Medications and Therapies ........................................................................45 
5.4.3. 
Rescue Medication ......................................................................................................45 
5.4.4. 
Diet .............................................................................................................................46 
5.5. 
Screen and Baseline/Randomization Failures ............................................................46 
5.6. 
Criteria for Discontinuation or Withdrawal of a Subject ............................................46 
5.6.1. 
Withdrawal From the Study ........................................................................................46 
5.6.2. 
Discontinuation Due to Disease Worsening Criteria ..................................................47 
5.7. 
Discontinuation/Withdrawal of Study Drug ...............................................................47 
5.8. 
Lost to Follow-up .......................................................................................................48 
6. 
STUDY DRUG ...........................................................................................................49 
6.1. 
Study Drug Administration.........................................................................................49 
6.1.1. 
Description of Study Drug/Matching Placebo ............................................................49 
6.1.2. 
Dosing and Administration .........................................................................................49 
6.1.2.1. 
Dose Administration ...................................................................................................49 
6.1.2.2. 
Dose Titration .............................................................................................................49 
6.1.2.3. 
Dose Maintenance ......................................................................................................50 
6.1.2.4. 
Dose Taper ..................................................................................................................50 
6.1.2.5. 
Dose Reduction Criteria .............................................................................................51 
6.1.2.6. 
Criteria for Dose Adjustment Following a Dose Reduction .......................................51 
6.2. 
Preparation/Handling/Storage/Accountability ............................................................51 
6.2.1. 
Acquisition and Accountability ..................................................................................51 
6.2.2. 
Formulation, Appearance, Packaging, and Labeling ..................................................52 
6.2.3. 
Study Drug Storage and Stability ...............................................................................52 
6.2.4. 
Study Drug Preparation ..............................................................................................52 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ........................................52 


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7. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................53 
7.1. 
Efficacy Assessments .................................................................................................53 
7.1.1. 
Seizure Assessments ...................................................................................................53 
7.1.2. 
Caregiver Diary ..........................................................................................................53 
7.1.3. 
CaGI-S and CaGI-C Scales ........................................................................................54 
7.1.4. 
CGI-C Scale ................................................................................................................54 
7.1.5. 
Quality of Life Scales .................................................................................................54 
7.1.5.1. 
PedsQL .......................................................................................................................54 
7.1.5.2. 
Parent/Caregiver Quality of Life ................................................................................54 
7.1.6. 
Behavior and Development Assessments ...................................................................55 
7.1.6.1. 
ABAS-3 ......................................................................................................................55 
7.1.6.2. 
BSID-III ......................................................................................................................55 
7.1.7. 
Sleep Quality ..............................................................................................................55 
7.2. 
Safety, PK, and Other Assessments ............................................................................55 
7.2.1. 
Physical and Neurologic Examinations ......................................................................55 
7.2.2. 
Vital Signs, Weight, and Height .................................................................................56 
7.2.3. 
ECG Measurements ....................................................................................................56 
 
 
 
 
7.2.6. 
Assessment of Suicidal Ideation .................................................................................57 
7.2.7. 
Clinical Laboratory Tests ...........................................................................................57 
7.2.8. 
PK and ASM Blood Samples .....................................................................................58 
 
 
 
 
 
 
7.2.10. 
Estimated Blood Volume Collection ..........................................................................60 
7.2.11. 
Study Drug Compliance .............................................................................................61 
7.3. 
AEs and SAEs .............................................................................................................61 
7.3.1. 
Definition of AEs ........................................................................................................61 
7.3.2. 
Definition of SAEs .....................................................................................................62 
7.3.3. 
Classifications of an AE .............................................................................................62 
7.3.3.1. 
Severity of Event ........................................................................................................62 
7.3.3.2. 
Causal Relationship to Study Intervention .................................................................62 


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7.3.3.3. 
Expectedness ...............................................................................................................63 
7.3.4. 
Time Period and Frequency for Event Assessment and Follow-up ...........................63 
7.3.4.1. 
AE Reporting ..............................................................................................................64 
7.3.4.2. 
SAE Reporting ............................................................................................................64 
7.3.4.3. 
Reporting Events to Participants ................................................................................64 
7.3.4.4. 
Events of Special Interest ...........................................................................................65 
7.3.5. 
Reporting of Pregnancy ..............................................................................................66 
8. 
STATISTICAL CONSIDERATIONS .......................................................................67 
8.1. 
Randomization ............................................................................................................67 
8.2. 
Sample Size Determination ........................................................................................67 
8.3. 
Populations for Analyses ............................................................................................67 
8.3.1. 
mITT Population .........................................................................................................67 
8.3.2. 
Per Protocol Population ..............................................................................................68 
8.3.3. 
Safety Population ........................................................................................................68 
8.4. 
Statistical Analyses .....................................................................................................68 
8.4.1. 
General Approach .......................................................................................................68 
8.4.2. 
Analysis of the Primary Efficacy Endpoint ................................................................68 
8.4.3. 
Analysis of the Secondary Efficacy Endpoints ..........................................................69 
8.4.4. 
Multiplicity Issues ......................................................................................................70 
8.4.5. 
Analysis of Additional Efficacy Endpoints ................................................................70 
8.4.6. 
Handling of Missing Data for the Primary Endpoint ..................................................70 
8.4.7. 
Safety Analyses ..........................................................................................................70 
8.4.7.1. 
Exposure .....................................................................................................................71 
8.4.7.2. 
AEs .............................................................................................................................71 
8.4.7.3. 
Laboratory Tests, Vital Signs, and ECGs ...................................................................71 
8.4.7.4. 
Other Safety Measures ................................................................................................72 
8.4.8. 
Baseline Measures ......................................................................................................72 
8.4.9. 
Planned Interim Analysis ............................................................................................72 
8.4.10. 
Tabulation of Individual Participant Data ..................................................................72 
8.4.11. 
PK Data Analysis ........................................................................................................72 
9. 
SUPPORTING DOCUMENTATION ........................................................................73 
9.1. 
Regulatory, Ethical, and Study Oversight Considerations .........................................73 
9.1.1. 
Informed Consent Process ..........................................................................................73 




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Table 3: 
Time Windows for Visits and Assessments ...............................................................28 
Table 4: 
Titration Scheme .........................................................................................................50 
Table 5: 
Clinical Laboratory Tests ...........................................................................................58 
 
 
 
 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schematic .............................................................................................20 
Figure 2: 
Pediatric Systemic Exposure Relative to Historical Adult Data ................................40 
 




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Study Population: 
Approximately 40 subjects diagnosed with KCNQ2-DEE, aged 1 month to 
less than 6 years. 
Study Duration: 
Subjects will undergo: 
• 
Screening/Baseline period – Minimum of 2 or 4 weeks duration 
(based on seizure frequency). 
− 
Additional time (2 weeks) may be added to the 
screening/baseline period at the discretion of the 
investigator to ensure adequate establishment of baseline 
seizure frequency (see Establishment of Baseline Seizure 
Frequency below). 
• 
Treatment period – Up to approximately 15 weeks (titration 
and maintenance). 
− 
Titration period – 24 days. 
− 
Maintenance period – 12 weeks. 
• 
Taper period – Up to 15 days. 
The study drug should be tapered over a period of up to 
15 days at any point a decision is made that a subject will 
discontinue study dosing, for any reason. This includes: 
− 
 
 
 
 
• 
Follow-up – Approximately 4 weeks after subjects have 
tapered off of study drug. 
Total study duration per subject is estimated to be: 
• 
Approximately 17 to 21 weeks for subjects who complete the 
maintenance period and enroll in the OLE. 
• 
Approximately 23 to 27 weeks for subjects who complete the 
maintenance period and do not enroll in the OLE. 
Study Design: 
Design: Randomized, double-blind, placebo-controlled, parallel group. 
Allocation: Randomization 1:1 (XEN496: placebo). 
Intervention: Parallel assignment. 
Blinding: Including subject, parents/guardians, caregivers, outcomes 
assessors/adjudicators, investigators, and sponsor. Designated pharmacy 
staff may be unblinded as appropriate. 
Baseline Period: 
Screening: Subjects will be screened (Visit 1) prior to entering the study 
and starting the baseline period. The parent(s)/guardian(s) of each subject 
will receive verbal and written information followed by signing of the ICF 






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global brain malformation. Brain MRI changes that are 
described as being associated with the KCNQ2-DEE and 
presumed to be secondary to the disease itself, will not be 
exclusionary. 
• 
Must have had 
focal tonic or other countable motor seizures 
in the month (28 days) prior to screening, documented by 
caregiver report or investigator medical notes. 
• 
Subjects will be taking 1 and no more than 4 concomitant 
ASMs. All doses must be stable for at least 1 week prior to 
screening and expected to be maintained throughout the 
duration of the study (until the end of the treatment period). 
• 
VNS is allowed and will not be counted as a concomitant 
ASM. The VNS device must be implanted for at least 6 months 
before screening, and the device settings must be stable for at 
least 6 weeks prior to screening and throughout the duration of 
the study. Use of the VNS device magnet is allowed. 
• 
Ketogenic diet is allowed and will not be counted as a 
concomitant ASM. The subject must be on a stable dietary 
regimen that produces ketosis for at least 6 weeks prior to 
screening and is expected to maintain the regimen throughout 
the study. 
Main Criteria for Exclusion: 
• 
Presence of a pathogenic or likely pathogenic variant in an 
additional gene associated with other epilepsy syndromes. 
(Variants in other epilepsy-associated genes that are not known 
to be pathogenic or are not likely to be pathogenic based upon 
adjudication review will not be a basis for exclusion.) 
• 
Presence of a known gain-of-function variant in the KCNQ2 
gene, or clinical characteristics consistent with previously 
reported pathogenic gain-of-function variants in the KCNQ2 
gene, such as subjects with infantile spasms without a history 
of neonatal-onset seizures. 
• 
Seizures secondary to infection, neoplasia, demyelinating 
disease, degenerative neurological disease, or central nervous 
system disease deemed progressive, metabolic illness, or 
progressive degenerative disease. 
• 
Confirmed diagnosis of infantile spasms within the past month 
prior to screening. 
• 
History or presence of any significant medical or surgical 
condition or uncontrolled medical illness at screening 
including, but not limited to, cardiovascular, gastrointestinal, 










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STATISTICAL ANALYSIS PLAN
Available upon request.