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

Primary Purpose

Epilepsy, Epilepsy in Children, Epilepsy; Seizure

Status

Active

Phase

Phase 3

Locations

International

Study Type

Interventional

Intervention

XEN496

Placebo

About this trial

This is an interventional treatment trial for Epilepsy focused on measuring XEN496, Ezogabine, Retigabine, Encephalopathy, Seizure, KCNQ2, EPIK

Eligibility Criteria

1 Month - 6 Years (Child)All SexesDoes not accept 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.

Sites / Locations

Children's Hospital of Philadelphia
MultiCare Health System - Mary Bridge Pediatrics - Tacoma
Sydney Children's Hospital
Universitair Ziekenhuis Antwerpen - Dienst Kinderneurologie

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Stage 1: Blinded Dose Transition/Titration

Stage 2: Open-Label Treatment

Arm Description

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

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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

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.

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

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

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.

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.

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.

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.

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".

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.

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.

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

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

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.

Full Information

NCT ID

NCT04912856

First Posted

May 3, 2021

Last Updated

June 26, 2023

Sponsor

Xenon Pharmaceuticals Inc.

1. Study Identification

Unique Protocol Identification Number

NCT04912856

Brief Title

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

Acronym

EPIK-OLE

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

June 2023

Overall Recruitment Status

Active, not recruiting

Study Start Date

August 17, 2021 (Actual)

Primary Completion Date

September 2023 (Anticipated)

Study Completion Date

November 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Xenon Pharmaceuticals Inc.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. 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).

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

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

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 3

Interventional Study Model

Sequential Assignment

Masking

ParticipantCare ProviderInvestigatorOutcomes Assessor

Masking Description

Patients will enter a blinded titration period (24 days) before moving to the open label treatment period for the remaining 35 months.

Allocation

Non-Randomized

Enrollment

8 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Stage 1: Blinded Dose Transition/Titration

Arm Type

Experimental

Arm Description

Arm Title

Stage 2: Open-Label Treatment

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

XEN496

Other Intervention Name(s)

ezogabine, retigabine

Intervention Description

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.

Intervention Type

Drug

Intervention Name(s)

Placebo

Intervention Description

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.

Primary Outcome Measure Information:

Title

Incidence of Adverse Events (AEs) and Serious Adverse Events (SAEs) related to intervention

Description

Safety and tolerability of XEN496 as assessed by incidence and severity of AEs and SAEs

Time Frame

From Screening/Baseline through to 4 weeks post last dose

Secondary Outcome Measure Information:

Title

Change in monthly countable motor seizure frequency

Description

Time Frame

Screening/Baseline to first 15 weeks (up to Visit 10)

Title

Description

Time Frame

Every three months from screening/baseline through to study completion, up to 162 weeks

Title

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

Description

Time Frame

Every three months from screening/baseline through to study completion, up to 162 weeks

Title

Description

Time Frame

Every three months from screening/baseline through to study completion, up to 162 weeks

Title

Change over time in Caregiver Global Impression of Severity (CaGI-S) scores for the subject's overall condition and for seizures.

Description

Time Frame

Study days: 1, 24, 67, 109, 182, 273, 364, 455, 546, 637, 728, 819, 910, 1001 and 1092

Title

Change over time in Caregiver Global Impression of Change (CaGI-C) scores for the subject

Description

Time Frame

Study days: 24, 67, 109, 182, 273, 364, 455, 546, 637, 728, 819, 910, 1001 and 1092

Title

Change over time in neurocognitive development based on the Bayley Scales of Infant and Toddler Development III (BSID-III)

Description

Time Frame

Study days: 1, 109, 364, 728 and 1092

Title

Change over time in adaptive behavior based on the Adaptive Behavior Assessment System, Third Edition (ABAS-3)

Description

Time Frame

Study days: 1, 109, 182, 364, 546, 728, 910 and 1092

Title

Change over time in the Investigator's Clinical Global Impression of Change scale (CGI-C) scores for the subject's seizures and overall condition

Description

Time Frame

Study days: 67, 109, 182, 364, 546, 728, 910 and 1092

Title

Use of rescue medication

Description

Time Frame

From screening/baseline through to study completion, up to 162 weeks

Title

Use of all concomitant medications including treatments used for seizure control

Description

Time Frame

From screening/baseline through to 162 weeks

Title

Change in the Pediatric Quality of Life Inventory scale in subjects with KCNQ2-DEE

Description

Time Frame

Study days: 1, 67, 109, 182, 546, 728, 910 and 1092

Title

Change in Pediatric Quality of Life Inventory, Family Impact scale in subjects with KCNQ2-DEE

Description

Time Frame

Study days: 1, 67, 109, 182, 546, 728, 910 and 1092

Title

Plasma concentrations of ezogabine and N-acetyl metabolite of ezogabine (NAMR)

Description

Blood samples will be taken at predefined visit dates to analyze the plasma concentrations.

Time Frame

Study days: 1, 16, 32, 67, 109, 182, 546, 728, 910 and 1092

10. Eligibility

Sex

All

Minimum Age & Unit of Time

1 Month

Maximum Age & Unit of Time

6 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Study Director

Organizational Affiliation

Xenon Pharmaceuticals Inc.

Official's Role

Study Director

Facility Information:

Facility Name

Children's Hospital of Philadelphia

City

Philadelphia

State/Province

Pennsylvania

ZIP/Postal Code

19104

Country

United States

Facility Name

MultiCare Health System - Mary Bridge Pediatrics - Tacoma

City

Tacoma

State/Province

Washington

ZIP/Postal Code

98405

Country

United States

Facility Name

Sydney Children's Hospital

City

Sydney

State/Province

New South Wales

ZIP/Postal Code

2031

Country

Australia

Facility Name

Universitair Ziekenhuis Antwerpen - Dienst Kinderneurologie

City

Edegem

State/Province

Antwerpen

ZIP/Postal Code

2650

Country

Belgium

12. IPD Sharing Statement

Links:

URL

https://clinicaltrials.gov/ct2/show/NCT04639310

Description

XPF-009-301 Study (EPIK)

Learn more about this trial

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

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