An Open-Label Extension of the Study XEN496 (Ezogabine) in Children With KCNQ2-DEE

Study Overview
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Brief Summary
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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
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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.

Official Title
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An Open-Label Extension of the Study XEN496 in Children With KCNQ2 Developmental and Epileptic Encephalopathy

Conditions
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Epileptic Syndromes, Epilepsy, Epilepsy in Children, Disease, Epilepsy; Seizure, Brain Diseases, Central Nervous System Diseases, Nervous System Diseases

Intervention / Treatment
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* Drug: XEN496
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subject completed participation 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. The caregiver is willing and able to be compliant with diary completion, visit schedule, and study drug administration. 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. Exclusion Criteria: Any adverse event(s) or serious adverse event(s) during the primary 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 study. 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 a risk to the subject if s/he were to enter the study. Any conditions that were specified as exclusion criteria in the primary study, XPF-009-301. It is anticipated that the subject will require treatment with at least 1 of the disallowed medications during the study. Any change in cardiac rhythm or atrioventricular conduction in the primary study that, in the investigator's opinion, is a significant risk to subject safety.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 6 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stage 1: Blinded Dose Transition/Titration<br>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. 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 will be required to taper off study drug over a period of up to 15 days | Drug: XEN496<br>* 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.<br>* Other names: retigabine;Drug: Placebo<br>* 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.<br>|
| Experimental: Stage 2: Open-Label Treatment<br>Optimally-tolerated dose level established during the transition/titration period will be maintained throughout the duration of open-label period unless dose adjustment is required. Subjects who discontinue or complete the study treatment will be required to taper off study drug over a period of up to 15 days. | Drug: XEN496<br>* 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.<br>* Other names: retigabine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) related to intervention | Safety and tolerability of XEN496 as assessed by incidence and severity of AEs and SAEs | From Screening/Baseline through to 4 weeks post last dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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 | Screening/Baseline to first 15 weeks (up to Visit 10) | 
| 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 | Caregivers will be instructed on how to complete the diary and will be asked to record information daily in the diary. Information on the number and type of countable motor seizures will be collected daily. | Every three months from screening/baseline through to study completion, up to 162 weeks | 
| Percent change from baseline in countable motor seizure frequency, relative to pre-randomization baseline of the primary study, XPF-009-301, assessed over time every 3 months during the OLE | Caregivers will be instructed on how to complete the diary and will be asked to record information daily in the diary. Information on the number and type of countable motor seizures will be collected daily. | Every three months from screening/baseline through to study completion, up to 162 weeks | 
| Percent change from baseline in countable motor seizure frequency, relative to pre-randomization baseline of the primary study, XPF-009-301, every 3 months based on combined data from both primary and OLE studies, by treatment group in the primary study | Caregivers will be instructed on how to complete the diary and will be asked to record information daily in the diary. Information on the number and type of countable motor seizures will be collected daily. | Every three months from screening/baseline through to study completion, up to 162 weeks | 
| Change over time in Caregiver Global Impression of Severity (CaGI-S) scores for the subject's overall condition and for seizures. | CaGI-S scale is Caregiver-reported assessment of the severity of the subject's seizures and overall condition over the previous 7 days. Responses to the CaGI-S questionnaire are to be rated on a 5 item Likert scale ranging from none to very severe. | Study days: 1, 24, 67, 109, 182, 273, 364, 455, 546, 637, 728, 819, 910, 1001 and 1092 | 
| Change over time in Caregiver Global Impression of Change (CaGI-C) scores for the subject | CaGI-C scale is a caregiver-reported assessment for the subject's overall condition and for seizures. Responses to the CaGI-C questionnaire are to be rated on a 7 item Likert scale ranging from very much improved to very much worse. | Study days: 24, 67, 109, 182, 273, 364, 455, 546, 637, 728, 819, 910, 1001 and 1092 | 
| Change over time in neurocognitive development based on the Bayley Scales of Infant and Toddler Development III (BSID-III) | The BSID-III is designed to identify young children with development delays, and assesses developmental function across 5 domains: cognition; language (expressive and receptive); motor (fine and gross motor functioning); social-emotional, and adaptive behavior. | Study days: 1, 109, 364, 728 and 1092 | 
| Change over time in adaptive behavior based on the Adaptive Behavior Assessment System, Third Edition (ABAS-3) | On a 4-point response scale, raters indicate whether, and how frequently, the individual performs each activity. The ABAS-3 assesses up to 11 skill areas: communication, community use, functional academics, health and safety, home or school living, leisure, motor, self-care, self-direction, social, and work. | Study days: 1, 109, 182, 364, 546, 728, 910 and 1092 | 
| Change over time in the Investigator's Clinical Global Impression of Change scale (CGI-C) scores for the subject's seizures and overall condition | The CGI-C consists of single items relating to each concept and is scored by the investigator using a 7-point Likert scale ranging from 1 to 7, anchored at 1 = Very much improved and 7 = Very much worse. | Study days: 67, 109, 182, 364, 546, 728, 910 and 1092 | 
| Use of rescue medication | Caregivers will be instructed on how to complete the diary and will be asked to record information daily in the diary. Information on the number and type of rescue medications will be collected daily. | From screening/baseline through to study completion, up to 162 weeks | 
| Use of all concomitant medications including treatments used for seizure control | Caregivers will be instructed on how to complete the diary and will be asked to record information daily in the diary. Information on the number and type of concomitant medications will be collected daily. | From screening/baseline through to 162 weeks | 
| Change in the Pediatric Quality of Life Inventory scale in subjects with KCNQ2-DEE | A modular instrument designed to measure health-related quality of life in both healthy and chronically ill children. The scales include parent-reported measures of the child's physical functioning, physical symptoms, emotional functioning, social functioning, and cognitive functioning | Study days: 1, 67, 109, 182, 546, 728, 910 and 1092 | 
| Change in Pediatric Quality of Life Inventory, Family Impact scale in subjects with KCNQ2-DEE | To evaluate the impact of pediatric chronic health conditions on parents and the family including measures of parent self-reported physical, emotional, social and cognitive function, communication and worry, in addition to family daily activities and family relationships | Study days: 1, 67, 109, 182, 546, 728, 910 and 1092 | 
| Plasma concentrations of ezogabine and N-acetyl metabolite of ezogabine (NAMR) | Blood samples will be taken at predefined visit dates to analyze the plasma concentrations. | Study days: 1, 16, 32, 67, 109, 182, 546, 728, 910 and 1092 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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XEN496, Ezogabine, Retigabine, Encephalopathy, Seizure, KCNQ2, EPIK