XEN496 (Ezogabine) in Children With KCNQ2 Developmental and Epileptic Encephalopathy (EPIK)

A Phase 3 Study of Adjunctive XEN496 in Pediatric Subjects With KCNQ2 Developmental and Epileptic Encephalopathy

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

Study Overview

• Status: Terminated
• Conditions: Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Epilepsy; Epileptic Syndromes; Disease; Epilepsy; Seizure; Epilepsy in Children
• Intervention / Treatment: Drug: XEN496; Drug: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 8
• Phase: Phase 3

Contacts and Locations

Study Locations

• Australia
  • New South Wales
    • Sydney, New South Wales, Australia, 2031
      • Sydney Children's Hospital
  • Queensland
    • South Brisbane, Queensland, Australia, 4101
      • Children's Health Queensland Hospital and Health Service
  • Victoria
    • Heidelberg, Victoria, Australia, 3084
      • Austin Health
• Belgium
  • Antwerpen
    • Edegem, Antwerpen, Belgium, 2650
      • Universitaire Ziekenhuis Anterpen - Dienst Kinderneurologie
• Italy
  • Genova, Italy, 16147
    • Istituto Giannina Gaslini
  • Milan, Italy, 20154
    • U.O.C. Neurologia Pediatrica Ospedale dei Bambini V. Buzzi
  • Verona, Italy, 37126
    • Azienda Ospedaliera Universitaria Integrata di Verona
• Spain
  • Madrid, Spain, 28009
    • Hospital Niño Jesús
  • Barcelona
    • Esplugues de Llobregat, Barcelona, Spain, 08950
      • Universitat de Barcelona - Hospital Sant Joan de Deu Barcelona (HSJDB)
• United States
  • California
    • Orange, California, United States, 92868
      • Children's Hospital of Orange County
    • San Francisco, California, United States, 94158
      • UCSF Medical Center
  • Colorado
    • Aurora, Colorado, United States, 80045
      • Children's Hospital of Colorado
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Children's National Health System
  • Florida
    • Gulf Breeze, Florida, United States, 32561
      • Northwest Florida Clinical Research Group
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Anne & Robert H. Lurie Children's Hospital
  • New York
    • New York, New York, United States, 10032
      • Columbia University Irving Medical Center
  • Ohio
    • Cleveland, Ohio, United States, 44195
      • The Cleveland Clinic Foundation
  • Oregon
    • Portland, Oregon, United States, 97239
      • Oregon Health and Science University
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19104-4318
      • Children's Hospital of Philadelphia
  • Washington
    • Tacoma, Washington, United States, 98405
      • MultiCare Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 month to 6 years (Child)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Male or female subjects aged from 1 month to less than 6 years, with a body weight of ≥3.0 kg at screening.
• Documented evidence of a genetic test result from an appropriately accredited laboratory, consistent with a diagnosis of KCNQ2-DEE (pathogenic, likely pathogenic, variant of unknown significance, or inconclusive but unlikely to support an alternate diagnosis).
• Seizure onset within 2 weeks after birth and EEG and documented clinical history consistent with KCNQ2-DEE.
• Magnetic resonance imaging has been performed and is without evidence of structural abnormalities, including but not limited to, hypoxia, hypoxia-ischemia, ischemia (arterial or venous), stroke, sinovenous thrombosis, intracranial hemorrhage, or focal or 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 28 days prior to screening.
• Taking 1 and no more than 4 concomitant antiseizure medications (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.
• Vagal nerve stimulation (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. Must must be on a stable dietary regimen that produces ketosis for at least 6 weeks prior to screening, and expected to be maintained throughout the study.
• Additional inclusion criteria apply, and will be assessed by the study team.

Exclusion Criteria:

• 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.
• Seizures secondary to infection, neoplasia, demyelinating disease, degenerative neurological disease, or Central nervous system (CNS) 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, hematologic, hepatic, ocular, pulmonary, renal, or urogenital systems, or other conditions that would not justify the subject's participation in the study, as determined by the investigator's risk benefit assessment.
• QT interval corrected for heart rate by Fridericia's formula (QTcF) of >440 msec. In addition, subjects with a history of arrhythmia, prolonged QT, heart disease or subjects taking medications known to increase the QT interval.
• History of hyperbilirubinemia, which lasts longer than 1 week will require exclusion of hepatic disease before entering the study.
• History of bilirubin-induced neurological dysfunction.
• Current disturbance of micturition or known urinary obstructions or history of bladder or urinary dysfunction including abnormal post-void residual bladder ultrasound, vesicoureteral reflux, urinary retention, or required urinary catheterization in the preceding 6 months.
• Known to have a terminal illness.
• Any clinically significant laboratory abnormalities or clinically significant abnormalities on pre-study physical examination, vital signs, or ECG that in the judgment of the investigator indicates a medical problem that would preclude study participation.
• Planned to begin a ketogenic or other specialized dietary therapy during the study.
• Caregiver history of chronic noncompliance with their child's prescribed drug regimens that has not been corrected.
• Exposure to any other investigational drug or device within 5 half-lives or 30 days prior to screening, whichever is longer or plans to participate in another drug or device trial at any time during the study.
• Concurrent enrollment in any other type of medical research judged by the investigator not to be scientifically or medically compatible with this study.
• Using felbamate presenting with clinically significant abnormalities and/or hepatic dysfunction during felbamate treatment, and subjects who have taken felbamate for less than 6 months prior to screening.
• Currently taking adrenocorticotropic hormone.
• Did not tolerate ezogabine when taken previously.
• Subjects with a known hypersensitivity to ezogabine or any of the excipients in the study drug.
• Other exclusion criteria apply, and will be assessed by the study team.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: XEN496; 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.	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 TID.; Other Names: ezogabine; retigabine
Placebo Comparator: Placebo; 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.	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 TID.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change From Baseline in Monthly (28 Day) Countable Motor Seizure Frequency During the Blinded Treatment Period	Parent/caregiver seizure diary record will be used to assess frequency, type and duration of seizure activity	From baseline to the end of the double-blind, 12 week treatment period (maintenance)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percentage of Subjects With ≥50 Percent Reduction in Monthly (28 Day) Seizure Frequency	Parent/caregiver seizure diary record will be used to assess frequency, type of seizure with a duration of at least 3 seconds.	From baseline to the end of the double-blind, 12 week treatment period (maintenance)
Caregiver Global Impression of Change (CaGI-C) Scores for the Subject's Overall Condition and for Seizures	CaGI-C scale is a caregiver-reported assessment of the change from baseline in the subject's overall condition and seizure severity. Responses to the CaGI-C questionnaire are to be rated on a 7-point Likert scale anchored at 1="Very much improved" and 7="Very much worse". Subjects at least minimally improved compared to baseline (a score of <=3) for overall condition or for seizure severity are reported in the analysis population. The primary comparison between treatments will be based on the last visit in the double-blind treatment period (or the early termination visit if the patient discontinued the treatment early). The results at Study Day 109 (end of treatment period) are provided.	Study Day 109
Change From Baseline in the Caregiver Global Impression of Severity (CaGI-S) 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-point Likert scale ranging from none to very severe. The CaGI-S consists of single items relating to each concept and is scored by the caregiver using a 5-point response ranging from 1 to 5, anchored at 1="None" and 5="Very Severe". Subjects with improvement of at least 1 level compared to baseline for overall condition or for seizure severity are reported in the analysis population. The results at Study Day 109 (end of treatment period) are provided.	Study Day 109

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety and Tolerability of XEN496 (e.g., Adverse Events) in Pediatric Subjects With KCNQ2-DEE	To assess adverse events as criteria for safety and tolerability	From screening through study completion (Day 109) or Day 151 for those not entering the OLE

Collaborators and Investigators

• Sponsor: Xenon Pharmaceuticals Inc.
• Investigators: Study Director: Study Director, Xenon Pharmaceuticals Inc.

Study record dates

Study Major Dates

• Study Start (Actual): March 29, 2021
• Primary Completion (Actual): May 16, 2023
• Study Completion (Actual): May 16, 2023

Study Registration Dates

• First Submitted: November 4, 2020
• First Submitted That Met QC Criteria: November 19, 2020
• First Posted (Actual): November 20, 2020

Study Record Updates

• Last Update Posted (Actual): August 23, 2024
• Last Update Submitted That Met QC Criteria: August 21, 2024
• Last Verified: August 1, 2024

More Information

Terms related to this study

• Keywords: Retigabine; Encephalopathy; Seizure; XEN496; Ezogabine; KCNQ2
• Additional Relevant MeSH Terms: Neurologic Manifestations; Epilepsy; Nervous System Diseases; Seizures; Brain Diseases; Epileptic Syndromes; Central Nervous System Diseases; Molecular Mechanisms of Pharmacological Action; Membrane Transport Modulators; Anticonvulsants; Ezogabine
• Other Study ID Numbers: XPF-009-301; 2020-002396-35 (EudraCT Number)

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No