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

Sponsor

Xenon Pharmaceuticals Inc. (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04912856

Collaborator

(none)

Enrollment

Location

Arms

27.5

Anticipated Duration (Months)

1.5

Patients Per Site Per Month

Study Details

Study Description

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).

Condition or Disease	Intervention/Treatment	Phase
Epilepsy Epilepsy in Children Epilepsy; Seizure Disease Brain Diseases Central Nervous System Diseases Nervous System Diseases Epileptic Syndromes	Drug: XEN496 Drug: Placebo	Phase 3

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 11 months.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

40 participants

Allocation:

Non-Randomized

Intervention Model:

Sequential Assignment

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Masking Description:

Patients will enter a blinded titration period (24 days) before moving to the open label treatment period for the remaining 11 months.

Primary Purpose:

Treatment

Official Title:

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

Actual Study Start Date :

Aug 17, 2021

Anticipated Primary Completion Date :

Dec 1, 2023

Anticipated Study Completion Date :

Dec 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Stage 1: Blinded Dose Transition/Titration 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. 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 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. Other Names: ezogabine retigabine Drug: Placebo 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.
Experimental: Stage 2: Open-Label Treatment 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 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. Other Names: ezogabine retigabine

Arm

Intervention/Treatment

Experimental: Stage 1: Blinded Dose Transition/Titration

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. 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

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.

Other Names:

ezogabine

retigabine

Drug: Placebo

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.

Experimental: Stage 2: Open-Label Treatment

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

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.

Other Names:

ezogabine

retigabine

Outcome Measures

Primary Outcome Measures

Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) related to intervention [From Screening/Baseline through to 4 weeks post last dose]
Safety and tolerability of XEN496 as assessed by incidence and severity of AEs and SAEs

Secondary Outcome Measures

Change in monthly countable motor seizure frequency [Screening/Baseline to first 15 weeks (up to Visit 10)]
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
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 [Every three months from screening/baseline through to study completion, up to 58 weeks]
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.
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 [Every three months from screening/baseline through to study completion, up to 58 weeks]
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.
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 [Every three months from screening/baseline through to study completion, up to 58 weeks]
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.
Change over time in Caregiver Global Impression of Severity (CaGI-S) scores for the subject's overall condition and for seizures. [Study days: 1, 24, 67, 109, 182, 273 and 364]
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.
Change over time in Caregiver Global Impression of Change (CaGI-C) scores for the subject [Study days: 24, 67, 109, 182, 273 and 364]
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.
Change over time in neurocognitive development based on the Bayley Scales of Infant and Toddler Development III (BSID-III) [Study days: 1, 109 and 364]
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.
Change over time in adaptive behavior based on the Adaptive Behavior Assessment System, Third Edition (ABAS-3) [Study days: 1, 109, 182 and 364]
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.
Change over time in the Investigator's Clinical Global Impression of Change scale (CGI-C) scores for the subject's seizures and overall condition [Study days: 67, 109, 182 and 364]
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".
Use of rescue medication [From screening/baseline through to study completion, up to 58 weeks]
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.
Use of all concomitant medications including treatments used for seizure control [Every three months from screening/baseline through to study completion, up to 58 weeks]
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.
Change in the Pediatric Quality of Life Inventory scale in subjects with KCNQ2-DEE [Study days: 1, 67, 109, 182 and 364]
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
Change in Pediatric Quality of Life Inventory, Family Impact scale in subjects with KCNQ2-DEE [Study days: 1, 67, 109, 182 and 364]
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
Plasma concentrations of ezogabine and N-acetyl metabolite of ezogabine (NAMR) [Study days: 1, 16, 32, 67, 109, 182 and 364]
Blood samples will be taken at predefined visit dates to analyze the plasma concentrations.

Eligibility Criteria

Criteria

Ages Eligible for Study:

1 Month to 6 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.